Audio Journal of Oncology Podcast: Recent Episodes
Audio Medica News
As the leading authoritative, peer-reviewed audio source of oncology clinical news for clinicians and healthcare professionals, the AJO Podcast regularly brings you exclusive interviews with the world's leading researchers and clinicians responsible for pushing out the boundaries of science and practice.
Medicine, screening, radiotherapy, surgery, clinical trials, cancer care, epidemiology and prevention are covered impartially to give busy cancer professionals access to conversational spoken comments on the clinical implications of cancer developments in the real-world context, as practiced by cancer doctors and clinicians around the globe.
The AJO Podcast originates from the Audio Journal of Oncology—staffed by ex-BBC professional journalists, and mentored by world-leading cancer practitioners from bodies including the American Society of Clinical Oncology, Cancer Research UK, Istituto Nazionale dei Tumori, and Action Radiotherapy.
Each podcast is produced to the highest standards of audio recording and journalism and is subject to editorial appraisal to maintain that content, balance and clinical relevance of news and comment are delivered in a manner that's easy and enjoyable for listening while travelling, taking exercise, working or just relaxing.
Please contact Audio Medica with your comments and make your contribution to supporting a vibrant community of clinical cancer communicators!
Patients with extensive stage small cell lung cancer did not live longer with thoracic radiotherapy added to their chemo-immunotherapy in a study reported to the American Society of Clinical Oncology 2026 Annual Meeting held in Chicago, USA.First author Bjørn Henning Grønberg MD PhD, Professor and Consultant in Oncology at the Norwegian University of Science and Technology, St. Olavs Hospital in Trondheim, Norway talked with the Audio Journal of Oncology about his group’s findings.
CHICAGO, USA—Combining the antibody-drug conjugate sacituzumab govitecan with pembrolizumab immunotherapy for patients with metastatic triple-negative breast cancers testing positive for the programmed death-ligand 1 (PD-L1) led to significant delays of disease progression after subsequent therapy in comparison with standard of care using a combination of chemotherapy with pembrolizumab.That’s according to first author of research reported at the 2026 American Association of Clinical Oncology Annual Meeting Kevin Kalinsky MD, Division Director of Breast Medical Oncology from Emory University at the Winship Cancer Institute, Hematology and Medical Oncology, in Atlanta, USA. He told reporter Peter Goodwin more about the details.
An interview with:Wing-Lok Chan MBBS, Clinical Associate Professor, Department of Clinical Oncology, The University of Hong Kong, Hong Kong, ChinaCHICAGO, USA—Patients with advanced cancer had their quality of life preserved and required fewer hospitalizations when they monitored themselves digitally by using the SUPPORT+ mobile phone app prompting better self-management while giving regular access to guidance from a nurse. This was in a randomized controlled study reported to the 2026 Annual Meeting of the American Society of Clinical Oncology by Wing-Lok Chan MBBS, from the Department of Clinical Oncology at the University of Hong Kong, in China. She talked about the findings with Peter Goodwin:
CHICAGO, USA—Patients with unresectable liver cancers who were eligible for treatment with transarterial chemoembolization (TACE), were randomly offered, treatment with the anti-CTL-4 checkpoint inhibitor tremelimumab together with the anti PD-L1 inhibitor durvalumab with or without a third drug: the multiple VEGFR 1, 2 & 3 kinase inhibitor, lenvatinib, in the phase threeEMERALD-3 study. Findings of a significant improvement of progression free survival were reported at the 2026 American Society of Clinical Oncology Annual Meeting by first author Ghassan Abou-Alfa MD PhD from the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, in New York and Weill Medical College, Cornell University, New York, NY. After his talk in Chicago Dr. Abou-Alfa gave Peter Goodwin the details:
Patients with RET Fusion Positive Early Stage Non-Small Cell Lung Cancer Benefit from Selpercatinib: LIBRETTO-432 Early Results An interview with: Jonathan W. Goldman MD, Director of Clinical Trials i
Abemaciclib Brings Marked Increase in Progression Free Survival for Patients with Advanced Dedifferentiated Liposarcoma An interview with: Mark A Dickson MD, Medical Oncologist, Associate Attending Ph
Omitting Axillary Lymph Node Dissection: Safe for Patients with Breast Cancer Spread to One or Two Sentinel Lymph Nodes An interview with: Jana de Boniface MD PhD Department of Surgery, Capio St. Göra
Timing of Surgery for Advanced Ovarian Cancer among Neoadjuvant and Adjuvant Chemotherapy Cycles: Early Findings from Randomized CHRONO Trial An interview with: Jean-Marc Classe, MD PhD, Surgeon in Gy
Giredestrant Beats Standard Endocrine Therapies Irrespective of Menopausal Status in Patients with ER+, HER2- Early Breast Cancer An interview with: Peter Schmid MD PhD, Professor of Cancer Medicine;
Immune Checkpoint Inhibitor-Induced Myocarditis within One Month Predicts Lethal “Triple M Overlap Syndrome” An interview with: Hassan Mohammed Abushukair MD, Post-Doctoral Researcher, Oklahoma Univer
BCMA-directed CAR T-cell Therapy Highly Effective In Patients with High-Risk Smoldering Multiple Myeloma An interview with: Omar Nadeem MD, Medical Oncologist and Clinical Investigator, Dana-Farber Ca
Molecular Glue Brings New Hope for Patients with BRAF or NRAS-Mutant Melanoma or Other RAS/RAF-driven Malignancies An interview with: Ahmad A Tahini MD PhD, Senior Member, Professor, Director, Departm
AI “Pathomics Platform” Selects Immunotherapy, Predicts Outcome for Patients with Metastatic Non-Small Cell Lung Cancer An interview with: Rukhmini Bandyopadhyay MD, Postdoctoral Fellow, The Universi
Investigational KRAS(ON) Inhibitor Zoldonrasib Showed Effective and Durable Responses in Patients With Advanced G12D-mutated Lung Cancer An interview with: Jonathan Wesley Riess MD, Professor of Medic
Whole Exome Sequencing of ctDNA Informs Post-Neoadjuvant Therapy Options for Patients with Triple Negative Early Breast Cancer An interview with: Marija Balic MD PhD, Chief of Medical Breast Oncology,
oral pre-cancer lesions injected with nivolumab prevented progression with little morbidity
New Generation KRAS G12C Inhibitor Brings Promising Responses Even in Patients with Advanced Lung Cancers Refractory to Previous KRAS-targeted Therapy An interview with Byoung Chul Cho MD PhD, Thoraci
“Molecular Glue Degrader Improves Outcomes in Heavily Pre-treated Patients with Advanced Solid Tumors” An interview with: Elena Garralda MD PhD, Medical Oncologist, Head, Early Drug Development Unit,
Safe to Avoid Endocrine Therapy in Older Women with Low Risk Breast Cancers: EUROPA Study Interim Findings An interview with: Icro Meattini MD, Associate Professor of Radiotherapy, University of Flore
Axillary Radiotherapy Seems As Effective as Axillary Lymphadenectomy in Sentinel Node Positive Early Breast Cancer, with Less Risk of Lymphedema An interview with: Amparo Garcia-Tejedor MD, PhD, Profe
Radiation Boost May No Longer Be Justified After Standard Therapy for Early Breast Cancer An interview with: Eline Verreck BSc, Erasmus University Medical Centre, Surgical Oncology Department, Rotterd
Fleur Mauritz MD discusses the 10-year follow-up findings from the RAPCHEM study, presented at the EBCC 2026. The research indicates that risk-based radiotherapy de-escalation is safe and effective following primary systemic therapy for early breast cancer patients. This approach allows for tailored treatment, potentially reducing side effects without compromising low recurrence rates. The study provides crucial long-term evidence supporting individualized radiotherapy strategies.
At the 2026 EBCC, Jelle Wesseling MD PhD discusses the LORD-trial, which found active surveillance for low-risk, estrogen-receptor-positive, HER2-negative, grade 1–2 DCIS is as effective as standard therapy. The trial's reassuring findings led to early cessation of randomization, supporting de-escal
Elisa Agostinetto MD presented at EBCC 2026, highlighting circulating tumor DNA (ctDNA) as a superior prognostic marker over clinical indicators for predicting relapse and progression in early breast cancer patients after neoadjuvant therapy. This research supports ctDNA for post-neoadjuvant risk st
Kerstin Wimmer MD, at the 2026 EBCC, discussed the OPBC-09 PRExRT study findings, revealing that polyurethane-coated breast implants significantly reduce capsular contracture risk for breast cancer patients receiving mastectomy with immediate pre-pectoral reconstruction followed by radiotherapy. Thi
At EBCC 2026, Fatima Cardoso MD discussed the OASIS-4 trial, revealing elinzanetant greatly reduced vasomotor symptoms ("hot flashes") in breast cancer patients receiving endocrine therapy. This dual neurokinin receptor antagonist demonstrated rapid and sustained efficacy across various ET types, of
Elisabetta Bonzano MD PhD discusses the BRAVE-HEART study at the 2025 EBCC, revealing how the Active Breathing Co-ordination (ABC) system significantly halves the coronary radiation dose during left breast irradiation. This crucial finding confirms ABC's high feasibility and clinical impact in reduc
This episode features Philip Poortmans MD PhD, University of Antwerp & Iridium Netwerk, discussing key themes from the 2026 European Breast Cancer Conference. He focuses on individualizing breast cancer therapy through de-escalation, covering the EUROPA trial, radiation boost data, axillary radiothe
Tess Snellen MD, from the Netherlands Cancer Institute, presents key findings at the EBCC 2026 regarding a molecular test. This innovative test utilizes next-generation sequencing to precisely differentiate between a recurrent ipsilateral breast cancer and a new primary tumor, significantly aiding i
Charles E Geyer MD, at ESMO 2025, discusses DESTINY-Breast05 results, revealing trastuzumab deruxtecan (T-DXd) significantly improves disease-free survival for HER2-positive early breast cancer patients with residual invasive disease after neoadjuvant therapy. T-DXd outperformed trastuzumab emtansin
Hope S. Rugo, MD, discusses the Phase III evERA Breast Cancer trial at SABCS 2025, revealing clinically meaningful improvements with giredestrant plus everolimus for ER-positive, HER2-negative metastatic breast cancer previously treated with a CDK4/6 inhibitor. Subgroup analyses show benefits regard
Othman Al-Sawaf MD PhD, a hematologist from University Hospital of Cologne, presents early data from the CLL17 international phase three trial at ASH 2025. The findings indicate that fixed-duration treatment with venetoclax plus obinutuzumab or venetoclax plus ibrutinib is non-inferior to continuous ibrutinib for patients with previously untreated chronic lymphocytic leukemia, potentially becoming the preferred treatment.
Dr. Juan Du presented early phase one study findings at ASH 2025, detailing a novel dual-targeted FasTCAR-T therapy for newly diagnosed multiple myeloma. The study demonstrated deep, durable responses in patients using the BCMA and CD19-targeting CAR T-cell platform, GC012F/AZD0120. These promising results, consistent across all dose groups, highlight a highly favorable safety profile and potential for patients, including those with high-risk features and transplant-ineligible individuals.
Thorsten Kühn MD PhD discusses findings from the AXSANA/EUBREAST 3(R) study at SABCS 2025. The research indicates that breast cancer patients who convert from clinically node-positive to node-negative after neoadjuvant chemotherapy do not require axillary lymph node dissection. Less invasive surgical staging procedures were found to be non-inferior in terms of three-year outcomes, irrespective of tumor type or initial stage.
This podcast episode, recorded at ASH 2025, features an interview with María-Victoria Mateos MD PhD, who discusses groundbreaking findings from the Majestec-3 study. The study highlights unprecedented survival benefits with the BCMA/CD3 bispecific antibody teclistamab. In patients with relapsed or refractory multiple myeloma, adding teclistamab to standard second-line therapies significantly improved progression-free and overall survival.
This episode features an interview with Erika Hamilton MD at the 2025 San Antonio Breast Cancer Symposium (SABCS). Dr. Hamilton discusses findings from the HER2CLIMB-05 trial, showing that adding tucatinib to trastuzumab and pertuzumab significantly improves progression-free survival in patients with HER2-positive metastatic breast cancer as first-line maintenance therapy, with no new safety signals. This small molecule HER2 inhibitor offers a promising new option.
Wojciech Jurczak MD PhD discusses research from ASH 2025, revealing that the non-covalent BTK inhibitor pirtobrutinib is superior to bendamustine plus rituximab as initial therapy for untreated chronic lymphocytic leukemia and small lymphocytic lymphoma. The BRUIN CLL-313 phase 3 study found pirtobrutinib significantly improved progression-free survival and was well-tolerated. These data suggest pirtobrutinib could become a new standard of care for these patients.
At SABCS 2025, Gaorav Gupta MD PhD presented findings from the TBCRC-053 (P-RAD) study. The research showed that pre-operative radiation therapy significantly increased T-cell infiltration in hormone receptor-positive, HER2-negative invasive breast cancer. This novel approach could enhance anti-tumor immunity and boost responses to systemic therapies like immunotherapy and chemotherapy in this common breast cancer subtype.
This episode discusses how the bispecific antibody Epcoritamab, in combination with rituximab and lenalidomide, has outperformed standard treatment for relapsed/refractory follicular lymphoma in the phase three epcore FL-1 trial. Dr. Lorenzo Falchi, an attending physician at Memorial Sloan Kettering, was interviewed at the ASH 2025 Annual Meeting, where these significant findings, including improved ORR and PFS, were presented, demonstrating a substantial reduction in the risk of progression or
Dr. Christian F. Singer discusses findings from the ABCSG 18 Study at the 2025 San Antonio Breast Cancer Symposium. The research indicates that post-menopausal women with ER-positive early breast cancer treated with denosumab and aromatase inhibitors show enhanced bone protection and improved long-term outcomes if their tumors are also positive for the progesterone receptor. This suggests PR-positive tumors drive the benefit of adjuvant denosumab.
An interview with Amir Fathi MD from Massachusetts General Hospital discusses the Paradigm study presented at ASH 2025. The phase two randomized trial found that young, fit adults with acute myeloid leukemia had improved event-free survival and higher response rates with azacitidine/venetoclax initial therapy. This gentler treatment also led to fewer toxicities and better quality of life compared to standard induction chemotherapy.
Dr. Jennifer A. Woyach discusses promising phase III study findings at ASH 2025, revealing that the non-covalent BTK inhibitor pirtobrutinib is as effective as ibrutinib, while demonstrating less toxicity, in patients with relapsed/refractory and treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma. This first randomized head-to-head comparison shows pirtobrutinib met its primary endpoint of non-inferiority for overall response rate.
Alexis Ann LeVee MD presented novel research at the 2025 San Antonio Breast Cancer Symposium. Her team's study, the randomized phase II neoHIP trial, revealed that pre-operative gut microbiome composition predicts pathologic complete response to immune checkpoint inhibition in patients with early-stage HER2-positive breast cancer. This highlights the microbiome's crucial role in influencing treatment outcomes for HER2-positive breast cancer.
Meletios Dimopoulos MD, Chair of Clinical Therapeutics at the University of Athens, discusses early findings from the phase 1b LINKER-MM2 trial presented at ASH 2025. The study reveals high clinical response rates for the B-Cell Maturation Antigen bispecific antibody linvoseltamab when combined with anti-CD38 therapy in patients with relapsed/refractory multiple myeloma. These preliminary safety and efficacy data support further development of this promising combination for MM treatment.
Antonio Jimenez Jimenez MD MS, from the University of Miami, presented findings at ASH 2025 indicating that donor choice is less of a barrier to allogeneic stem cell transplantation for patients with hematologic malignancies. The National Marrow Donor Program Access Trial found that post-transplant cyclophosphamide enables a wider, more ethnically diverse range of patients to safely receive transplants from unrelated donors.
Safna Naozer Virji MBBS FPBS was interviewed at the 2025 San Antonio Breast Cancer Symposium regarding her study on oncoplastic breast cancer surgery. Her research from Pakistan reported high efficacy and superior psychosocial outcomes for patients in low or middle-income settings. The study demonstrated low margin positivity, excellent long-term survival, and high patient-reported cosmetic satisfaction, supporting broader use of OBS in resource-limited areas.
Dr. Luciano Costa discusses the findings from the CARTITUDE-4 study at the ASH 2025 Annual Meeting in Orlando. The study demonstrates that ciltacabtagene autoleucel CAR-T cell therapy provides significant long-term progression-free survival for patients with standard-risk relapsed or refractory multiple myeloma, even as early as second-line treatment. The findings suggest profound benefits in this patient population.
Matteo Lambertini MD PhD discusses new findings from the ALTTO trial at the 2025 San Antonio Breast Cancer Symposium. The long-term analysis reveals that adjuvant aromatase inhibitors lead to superior outcomes, including improved disease-free survival and time to distant recurrence, compared to tamoxifen or other SERMs.
Dr. Jesse Tettero discusses findings from the HARMONY Alliance study, presented at ASH 2025, validating measurable residual disease (MRD) as a robust predictor of overall survival in acute myeloid leukemia (AML) patients. The study supports MRD's potential as a regulatory surrogate endpoint, particularly MFC-MRD in non-transplanted patients, to accelerate drug development. This large pooled analysis provides critical evidence for future AML drug approvals.
Dr. Hisham Abdel-Azim discusses findings from the phase two EndRAD trial, presented at ASH 2025. The study reveals that Next Generation Sequencing-Assessed Minimum Residual Disease (NGS-MRD) can identify young patients with high-risk/relapsed B-cell Acute Lymphoblastic Lymphomas (B-ALL) who can safely omit pre-transplant Total Body Irradiation (TBI). This approach achieved comparable survival outcomes while potentially reducing TBI-associated late effects.
Dramatic Cures for Children with No Prospects Using Standard Therapies for T-cell malignancies
Some patients being treated for stage three colon cancer could avoid the use of chemotherapy and be spared toxicities such as neuropathy: according to a study in which ctDNA liquid biopsy monitoring f
Chemo-Free Regimen with Neoadjuvant CDK 4/6 Inhibition plus Endocrine Therapy Benefits Patients with High-Risk ER+ HER2- Early Breast Cancer
An interview with: Paul H Cottu MD PhD, Medical Oncologist and Associate Professor, Institute Curie, Paris, France
BERLIN, Germany—Patients with high-risk, hormone receptor positive, HER2 negative early breast cancers, who would typically be candidates for chemotherapy, had good clinical responses, high biological responses and good rates of surgery in a clinical trial using a chemotherapy-free neoadjuvant regimen consisting of letrozole hormone therapy plus abemaciclib CDK 4/6 inhibition.
Medical Oncologist Paul Cottu MD PhD from the Institute Curie in Paris, France, reported findings from RIBOLARIS trial at the 2025 Annual Congress of the European Society for Medical Oncology held in Berlin. At his poster during the conference he talked about the study findings with Audio Journal of Oncology reporter Peter Goodwin:
AUDIO JOURNAL OF ONCOLOGY Paul H Cottu MD PhD
IN: “[GOODWIN] I am at the European ….. OUT: …I’m Peter Goodwin 7:56secs
ESMO ABTRACT 296O:
“Risk of recurrence (ROR) after neoadjuvant ribociclib plus ET in clinically high-risk ER+/HER2− BC: Preliminary analysis of the SOLTI-RIBOLARIS trial”
Speaker: Paul H. Cottu (Paris, France)
Authors:
Paul H. Cottu (Paris, France) Aleix Prat (Barcelona, Spain) Tomás Pascual (Barcelona, Spain) Huilin Hu (East Hanover, United States of America) Estelle Roux (Basel, Switzerland, NJ) Francisco Javier Salvador Bofill (Seville, Spain) Joana M. Ribeiro (Villejuif, France) Isabel Blancas López-Barajas (Granada, Spain) Thomas Bachelot (Lyon, France) Jerome Lemonnier (Paris, France) Juan M. Ferrero-Cafiero (Barcelona, Spain) Pablo Tolosa Ortega (Madrid, Spain, Valencia) Antonio Mulero-Sánchez (Barcelona, Spain) Thayane Antoniolli Crestani (Brussels, Belgium) Roisin M. Connolly (Cork, Ireland, MD) Cynthia X. Ma (St. Louis, United States of America) Antonio C. Wolff (Baltimore, United States of America, MD) Guillermo Villacampa (Barcelona, Spain) Thibault De La Motte Rouge (Rennes, France) Joaquín Gavilá-Gregori (Valencia, Spain)
Background
The CDK4/6 inhibitors (CDK46/i) are approved for early-stage HR+/HER2− breast cancer (BC). The randomized neoadjuvant NeoPAL and CORALLEEN trials provided proof of concept that CDK4/6i in combination with endocrine therapy (ET) have similar activity to multi-agent chemotherapy in pts with luminal B-PAM50 based- BC subtype. The PAM50-derived ROR score was identified as an endpoint of interest after neoadjuvant CDK4/6i-ET. The RIBOLARIS trial was designed to evaluate whether pts with ROR-low disease following neoadjuvant ribociclib (RIB) and ET can safely omit adjuvant chemotherapy.
Methods
RIBOLARIS is an open-label, single-arm, multicenter trial in pts with primary operable stage II, grade 2/3, Ki67 ≥20%, HR+/HER2− BC who are candidates for adjuvant chemotherapy. The study evaluates safety and long-term efficacy of a non-chemo regimen (RIB-ET) in pts with tumors showing a ROR-low score after 6 neoadjuvant cycles of RIB-ET (600 mg/day 3 weeks ON/1 week OFF + ET: letrozol 2.5 mg/day) followed by surgery (within 10 days). Pts with ROR-med/high tumors will receive chemotherapy-based treatment followed by RIB-ET. This preplanned Interim Analysis analyzed safety and efficacy after 686 surgeries. We expected at least 40% of the pts to achieve a ROR-low score after neoadjuvant RIB-ET.
Results
Among the enrolled pts, baseline characteristics included: median age 57 (38-84), postmenopausal status 62%, tumor stage IIA 60%, node-negative 60%, and histological grade 2 74%. At data cut-off, 686 out of 1100 surgeries (62.4%) were performed. Interestingly, we observed that 361 pts (52.6%) achieved a ROR-low score (Mean 11.3, 95% CI 10.5-12.2), while 325 pts (47.4%) had a med/high ROR score (Mean 36.9, 95% CI 34.2-39.5). The most common grade 3-4 severity TEAEs were neutropenia (grade 3: 46.3%; grade 4: 3.5%) and transaminases increased (grade 3: 10.4%; grade 4: 1.5%).
Conclusions
These preliminary results from the RIBOLARIS trial confirm and extend the findings from CORALLEEN and NeoPAL trials, demonstrating that a subset of pts with early-stage HR+/HER2− BC achieve ROR-low disease after neoadjuvant RIB-ET and may be candidate to spare chemotherapy. There was no new safety signal.
Clinical trial identification
NCT05296746.
An interview with Li Zhang MD, Medical Oncologist and Full Professor, Sun Yat-sen University Cancer Center, Guangzhou, China
BERLIN, Germany—A doubling of progression-free survival, and highly statistically significant benefit for overall survival, has been achieved in patients with epidermal growth factor- (EGFR-) mutated non-small cell lung cancers that had become refractory to EGFR tyrosine kinase inhibitor therapy in a study in which treatment with the antibody drug conjugate (ADC) sacituzumab tirumotecan was compared with standard platinum-based chemotherapy.
At the 2025 Annual Congress of the European Society for Medical Oncology (ESMO) Professor Li Zhang MD, a medical oncologist and full professor at Sun Yat-sen University Cancer Center in Guangzhou, China, reported findings from the randomized, multi-center phase III OptiTROP-Lung04 study at a late-breaking session. After his talk he discussed the findings with Audio Journal of Oncology reporter, Peter Goodwin:
AUDIO JOURNAL OF ONCLOGY: Li Zhang MD
IN: “[GOODWIN] I’m here at ……OUT: …..I’m Peter Goodwin 8:42 secs
ESMO ABSTRACT LBA5:
Sacituzumab tirumotecan (sac-TMT) vs platinum-based chemotherapy in EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) following progression on EGFR-TKIs: results from the randomized, multi-center phase III OptiTROP-Lung04 study
Speaker:
Li Zhang (Guangzhou, China)
Authors:
Li Zhang (Guangzhou, China) Wen Feng Fang (Guangzhou, China) Lin Wu (Changsha, China) Xiangjiao Meng (Jinan, China) Yu Yao (Xi’an, Shaanxi Province, China) Wei Zuo (Nanchang, China) Wenxiu Yao (Chengdu, China) Yanyan Xie (Nanning, China) Yu Zhang (Mianyang, China) Jiuwei Cui (Changchun, China) Yongchang Zhang (Changsha, China) Xingya Li (Zhengzhou, China) Wu Zhuang (Fuzhou, China) Jian Fang (Beijing, China) Qiming Wang (Zhengzhou, China) Wei Jiang (Nanning, China) Kai Li (Tianjin, China) Yina Diao (Chengdu, China) Junyou Ge (CHENGDU, China) Yunpeng Yang (Guangzhou, China)
Background
Sac-TMT is a TROP2 ADC developed with a novel linker to conjugate the payload, a belotecan-derivative topoisomerase I inhibitor. Sac-TMT demonstrated significant survival benefits over docetaxel in EGFRm NSCLC after failure of EGFR-TKI and platinum-based chemotherapy (Fang et al., BMJ 2025). Here, we first report the final PFS analysis and preplanned interim OS analysis results from the phase 3 OptiTROP-Lung04 study (NCT05870319).
Methods
Patients (pts) were randomized (1:1) to receive sac-TMT monotherapy (5 mg/kg Q2W) or chemotherapy (pemetrexed 500 mg/m2 + carboplatin AUC 5 or cisplatin 75 mg/m2 Q3W for 4 cycles followed by maintenance of pemetrexed). The primary endpoint was PFS assessed by blinded independent review committee (BIRC) with OS as a key secondary endpoint tested hierarchically.
Results
A total of 376 pts (median age 59.5 yrs; 39.6% male; 79.3% ECOG PS 1; 94.7% prior 3rd-generation EGFR TKI) were randomized to the sac-TMT (n=188) or chemotherapy (n=188) groups. At a median follow-up of 18.9 mo, 21.3% of pts (sac-TMT) vs 1.6% (chemotherapy) remained on treatment. Sac-TMT demonstrated highly statistically significant and clinically meaningful improvements in PFS and OS compared to chemotherapy (Table). Grade ≥ 3 TRAEs occurred in 49.5% and 52.2%, and TRSAEs in 7.4% and 17.0% of pts in sac-TMT and chemotherapy arms, respectively. No drug-related interstitial lung disease/pneumonitis occurred in either arm.
Sac-TMT (n=188) Chemotherapy (n=188)
Median PFS (BIRC), mo (95% CI) 8.3 (6.7 – 9.9) 4.3 (4.2 – 5.5)
HR (95% CI) 0.49 (0.39 – 0.62)
P-value <0.0001
12-mo PFS rate, %, (95% CI) 32.3 (25.5 – 39.2) 7.9 (4.4 – 12.8)
Median OS, mo (95% CI) NR (21.5 – NE) 17.4 (15.7 – 20.4)
HR (95% CI) 0.60 (0.44 – 0.82)
P-value 0.0006
Adjusted median OS*, mo (95% CI) NR (21.5 – NE) 17.2 (15.4 – 18.9)
HR (95% CI) 0.56 (0.41 – 0.77)
P-value 0.0002
ORR (BIRC), % (95% CI) 60.6 (53.3, 67.7) 43.1 (35.9, 50.5)
Median DOR (BIRC), mo (95% CI) 8.3 (6.2 – 10.0) 4.2 (3.0 – 4.4)
Data cutoff: Jul 06, 2025. P-value was presented as one-sided. *censored at the date of initiation of subsequent anti-tumor ADC drug therapy.
Conclusions
Sac-TMT is the first TROP2 ADC to significantly improve PFS and OS over platinum-based chemotherapy, with manageable safety in EGFR-TKI resistant NSCLC, positioning it as a potential new standard of care for this population.
Clinical trial identification
NCT05870319.
Legal entity responsible for the study
Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd.
An interview with: https://www.audiomedica.com/wp-content/2025/11/251019-Erwei-Song-ESMO-2025-PRODUCTION-MASTER.mp3, Director of Health Science Center, President, Sun Yat-sen Memorial Hospital, Guangzhou (SYSU), Guangzhou, China.
BERLIN, Germany—The open-label HORIZON-Breast01 phase-three study has reported early data showing that, for previously treated patients with advanced or metastatic breast cancer, progression-free survival improved from a median of 8.3 months with pyrotinib plus capecitabine standard of care to 30.6 months among patients in the experimental arm who received monotherapy with the new antibody drug conjugate (ADC) trastuzumab resetecan. Furthermore, the ADC had a favorable safety profile with low occurrence of interstitial lung disease (ILD).
Findings were reported at the 2025 Annual Congress of the European Society for Medical Oncology by Erwei Song MD PhD, Director of the Health Science Center, President, Sun Yat-sen Memorial Hospital, Guangzhou (SYSU), in Guangzhou, China. After his talk at the conference, Professor Song discussed the findings with Audio Journal of Oncology reporter Peter Goodwin:
Audio Journal of Oncology: Erwei Song MD PhD
IN: “[GOODWIN] I am at …… OUT: …….of Oncology, I’m Peter Goodwin. 7:42secs
ESMO ABSTRACT LBA19:
“SHR-A1811 versus pyrotinib plus capecitabine in human epidermal growth factor receptor 2-positive (HER2+) advanced/metastatic breast cancer (BC): A multicenter, open-label, randomized, phase III study (HORIZON-Breast01)”
Speaker: Erwei Song (Guangzhou, China)
Authors:
Erwei Song (Guangzhou, China) Herui Yao (Guangzhou, China) Huiping Li (Beijing, China) Yongmei Yin (Nanjing, China) Qing Yuan Zhang (Harbin, China) Shusen Wang (Guangzhou, China) Quchang Ouyang (Changsha, China) Tao Sun (Shenyang, Liaoning, China) Xiaojia Wang (Hangzhou, China) Weimin Xie (Nanning, China) Biyun Wang (Shanghai, China) Wei Li (Changchun, China) Min Yan (Zhengzhou, China) Cuizhi Geng (Shijiazhuang, China) Yuan Peng (Beijing, China) Yaping Yang (Guangzhou, China) Fangli Dong (Shanghai, China) Ying Zhang (Shanghai, China) Lin Cheng (Shanghai, China) Xiaoyu Zhu (Shanghai, China)
Background
SHR-A1811, a HER2-targeted antibody-drug conjugate, proved substantial single agent antitumor activity in heavily pretreated solid tumors as shown in a global phase 1 trial (J Clin Oncol. 2024). Here, we first report the interim analysis of SHR-A1811 versus pyrotinib plus capecitabine in HER2+ advanced/metastatic BC from the pivotal phase 3 HORIZON-Breast01 study.
Methods
Taxane- and trastuzumab-pretreated patients (pts) with HER2+ advanced/metastatic BC were randomized (1:1) to receive intravenous SHR-A1811 or oral pyrotinib plus capecitabine. The primary endpoint was PFS by blinded independent central review (BICR).
Results
As of Jun 30, 2025, 287 pts were randomized (SHR-A1811, n=142; pyrotinib plus capecitabine, n=145; IHC 3+: 76.1% vs. 71.7%; HR+: 47.9% vs. 47.6%; median lines of prior systemic treatments: 1 vs.1; prior pertuzumab: 71.8% vs. 72.4%), with median follow-up of 15.9 months (95% CI 14.6–17.1) for SHR-A1811, and 15.3 months (95% CI 14.3–16.6) for pyrotinib plus capecitabine. The PFS by BICR was significantly improved in the SHR-A1811 group than in the pyrotinib plus capecitabine group (30.6 months vs. 8.3 months; HR 0.22 [95% CI 0.15–0.34]; p<0.0001; table). Although the median OS was not yet reached, SHR-A1811 showed a clear OS benefit trend. Median treatment duration was 19.5 months (95% CI 17.3–NR) with SHR-A1811, 7.1 months (95% CI 5.6–9.2) with pyrotinib, and 7.5 months (95% CI 5.7–9.6) with capecitabine. Similar rates of TRAEs were observed. Interstitial lung disease (ILD) occurred only in 4 pts (2.8%) receiving SHR-A1811 (grade 1/2: 3 [2.1%]; grade 3: 1 [0.7%]).
Conclusions
SHR-A1811 exhibited significant PFS benefit and strong trend in OS benefit versus pyrotinib plus capecitabine in the second-line therapy in HER2+ advanced/metastatic BC, with favorable safety profile of low ILD occurrence.
Clinical trial identification
NCT05424835.
Legal entity responsible for the study
Jiangsu Hengrui Pharmaceuticals Co., Ltd.
Funding
Jiangsu Hengrui Pharmaceuticals Co., Ltd.
Disclosure
- Dong, Y. Zhang, L. Cheng, X. Zhu: Financial Interests, Personal, Full or part-time Employment: Jiangsu Hengrui Pharmaceuticals Co., Ltd.
An interview with: Andrew Clamp MD, PhD, Consultant Medical Oncologist, Christie Hospital, Manchester, UK
BERLIN, Germany—An important therapeutic gain in terms of overall- and progression-free survival has been achieved merely by changing the chemotherapy dose schedule given to patients with high-risk stage three or four epithelial ovarian cancer.
This was reported from the ICON8B: GCIG phase-three randomised trial by Andrew Clamp MD PhD of the Christie Hospital in Manchester, England, at the 2025 Annual Congress of the European Society for Medical Oncology. Dr. Clamp discussed the findings with our reporter, Peter Goodwin.
Audio Journal of Oncology interview: Andrew Clamp MD, PhD
IN: “[GOODWIN] I’m at the European ….. OUT: ….Journal of Oncology, I’m Peter Goodwin” 7:21secs
https://www.annalsofoncology.org/article/S0923-7534(25)02624-9/pdf
ESMO ABSTRACT:
1064O – ICON8B: GCIG phase III randomised trial comparing first-line weekly dose-dense chemotherapy + bevacizumab to three-weekly chemotherapy + bevacizumab in high-risk stage III-IV epithelial ovarian cancer (EOC): Final overall survival (OS) analysis
Speaker: Andrew R. Clamp (Manchester, United Kingdom)
Authors: Andrew R. Clamp (Manchester, United Kingdom) Iain McNeish (London, United Kingdom) Domenico Radice (London, United Kingdom) Rosemary Lord (Liverpool, United Kingdom) Agnieszka Michael (Guildford, United Kingdom, Surrey) Audrey Cook (Cheltenham, United Kingdom) Roshan Agarwal (Northampton, United Kingdom, Northamptonshire) Axel Walther (Bristol, United Kingdom) Sarah P. Blagden (Oxford, United Kingdom) Dearbhaile O’Donnell (Dublin, Ireland) James D. Brenton (Cambridge, United Kingdom) Sudha Sundar (Birmingham, United Kingdom) Cristiana Sessa (Bellinzona, Switzerland) Laura R. Murphy (London, United Kingdom) Francesca Schiavone (London, United Kingdom) Aleksandra Gentry-Maharaj (London, United Kingdom) Richard S. Kaplan (London, United Kingdom) Mahesh K. Parmar (London, United Kingdom, London) Jonathan A. Ledermann (London, United Kingdom)
ESMO Abstract
Background
In ICON8B the use of dose-dense weekly paclitaxel (ddwT) with 3-weekly (q3w) carboplatin (C) and bevacizumab (BEV) as first-line treatment improved median progression-free survival (PFS) by 5.5 months (m) compared to standard q3w paclitaxel (T) dosing with C+BEV (22.2m vs 16.7m; Hazard Ratio (HR) 0.75, 95% CI 0.62-0.90 p=0.002). We now report the final OS analysis conducted at trial closure.
Methods
Eligible participants (pts) with high-risk stage III (residual disease >1cm diameter after immediate primary surgery (IPS) or requirement for primary chemotherapy) or stage IV EOC were randomised 1:1:1 to Arm B1 (standard- q3w C AUC5/6+q3w T 175mg/m2+ q3w BEV 7.5mg/kg); Arm B2- (q3w C AUC5/6+ddwT 80mg/m2); Arm B3- (q3w C AUC5/6+ddwT 80mg/m2+ q3w BEV 7.5mg/kg). Up to six cycles chemotherapy and 18 BEV cycles were administered. Arm B2 recruitment discontinued after ICON8 saw no evidence of PFS improvement with q3wCddwT vs q3wCT. OS was a key secondary outcome and pts were followed for survival endpoints until trial closure on 18th Dec 2024 at end of academic funding.
Results
From 07/2015 to 03/2020 579 pts were randomised to arms B1 + B3. Median age was 64 years; 91% had High Grade Serous Carcinoma; 93% Stage IIIc/IV; 84% primary chemotherapy with planned delayed primary surgery, 14% IPS, 2% inoperable; 50.2% cases sequenced for germline BRCA1/2 mutations. After a median follow-up of 72.0m, 411 deaths were reported (197 in B3; 214 in B1). Median OS was 49.8m (95% CI 43·7-54.5m) in B3 and 39.6m (95% CI 34·7-45·0m) in B1 (HR 0·79, 95% CI 0·65-0·95, p=0·010). In pts receiving primary chemotherapy, median OS was 47.3m (95% CI 42.0-52.6m) in B3 and 37.1m (95% CI 32.3-42.1m) in B1.
Conclusions
In pts with high-risk stage III-IV EOC, the use of ddwT in combination with q3w C + BEV as first-line systemic therapy improves median OS by 10.2m compared to q3w T dosing. ddwT with q3wC+BEV should now be considered a standard-of-care first-line treatment option in this group. Further research is required to determine whether efficacy of this regimen is impacted by tumour homologous recombination deficiency and intrinsic chemosensitivity.
Clinical trial identification
ISRCTN10356387.
Legal entity responsible for the study
University College London.
Funding
Cancer Research UK and Medical Research Council.
An interview with Nima Nabavizadeh MD, Associate Professor of Radiation Medicine, Oregon Health & Science University (OHSU), Portland, USA, Chief Medical Officer, Cancer Early Detection Research Center, Portland, Oregon.https://www.audiomedica.com/wp-content/2025/11/251107-Nima-Nabavizadeh-MD-ESMO-2024-PRODUCTION-MASTER.mp3
BERLIN, Germany—A pan-cancer early detection test, that identifies “methylation fingerprints” for a wide range of cancers, has been shown to find more cancers sooner than conventional screening according to research reported to the European Society for Medical Oncology (ESMO) 2025 Annual Congress.
Nima Nabavizadeh MD, Associate Professor of Radiation Medicine at the Oregon Health & Science University (OHSU) in Portland, USA, who is also Chief Medical Officer of the Cancer Early Detection Research Center in Portland, Oregon gave a report on the safety and performance of the test at the ESMO congress. Afterwards he spoke with our reporter, Peter Goodwin:
Audio Journal of Oncology: Nima Nabavizadeh MD
IN: “[GOODWIN]I am at the ESMO meeting …. OUT: ……of oncology. I’m Peter Goodwin” 9:55sec
ESMO ABSTRACT LBA64:
Safety and performance of a multi-cancer early detection (MCED) test in an intended-use population: Initial results from the registrational PATHFINDER II study
https://assets.grail.com/wp-content/uploads/2025/10/ESMO-2025_PF2-Initial-Results_Presentation_FINAL-CLEAN-10.16.2025.pdf
Speaker:
Nima Nabavizadeh (Portland, United States of America)
Authors:
Nima Nabavizadeh (Portland, United States of America) Charles McDonnell III (Sacramento, United States of America) Dax Kurbegov (Nashville, United States of America) Marc Matrana (New Orleans, United States of America) Shirish Gadgeel (Detroit, United States of America) Raymond H. Kim (Toronto, Canada) Gretchen Stipec (Fountain Valley, United States of America) Kevin Oeffinger (Durham, United States of America) Michael J. Demeure (Newport Beach, United States of America) Roland Matthews (Atlanta, United States of America) Rebecca Kaltman (Fairfax, United States of America) Tamar Toronjadze (Flushing, United States of America) Cora N. Sternberg (New York, United States of America) Jennifer Tran (Washington, United States of America) Natalia Colocci (Mountain View, United States of America) Leonardo Forero (Amarillo, United States of America) Margarita Lopatin (Menlo Park, United States of America) Margaret McCusker (Menlo Park, United States of America) Karthik Giridhar (Rochester, United States of America)
Background
The MCED test (Galleri®) detects cancer signals from cell-free DNA in blood and predicts cancer signal origin (CSO) to guide diagnostic (dx) evaluation. PATHFINDER 2 (PF2; NCT05155605) assesses its safety and performance in a large, diverse intended-use population.
Methods
PF2 is a prospective, multicenter, interventional study that enrolled participants (ppts) aged ≥50y with no clinical suspicion of cancer and no cancer diagnosis/treatment in the past 3y. Primary objectives were safety and performance of the MCED test. Ppts with an MCED cancer signal detected (positive) result underwent dx evaluation based on predicted CSO(s). This prespecified initial analysis included ppts with 12m follow-up (fu) as of Dec 31, 2024. A 3y fu is planned.
Results
35,878 ppts were enrolled. Of 23,161 performance analyzable ppts with 12m fu, 216 (0.93%) had a positive MCED test. Specificity was 99.6% (95% CI 99.5-99.7%); positive predictive value (PPV) was 61.6% (54.9-67.8%). First CSO prediction accuracy was 91.7% (85.8-95.3%). Episode sensitivity during 12m fu was 73.7% (65.6-80.4%) in a prespecified subgroup of 12 cancers responsible for ⅔ of US cancer deaths and 40.4% (35.3-45.8%) in all cancers. Of 329 ppts with cancer, 200 had screen-detected cancers: 133 by MCED testing (114 new primaries; 19 recurrent), 20 by USPSTF A/B and 47 by USPSTF C recommended screening tests. Of 133 MCED-detected cancers (MCED cancer detection rate: 0.57%), 75.2% do not have common screening options. Of 114 MCED-detected new primaries, 53.5% were stage I-II; 69.3% were stage I-III. Median time to dx resolution was 46d (IQR 42-59). Of 25,114 safety analyzable ppts, 159 (0.6%) had a protocol-directed invasive procedure. Invasive procedures were ∼2x more common for ppts dx with cancer vs not dx after a positive MCED test.
Conclusions
MCED testing increased the number of screen-detected cancers nearly 7-fold when added to USPSTF A/B recommended screening (3-fold when added to USPSTF A/B/C). Most MCED-detected new primaries were early stage. With PPV exceeding that of standard of care screening tests and a favorable safety profile, these initial PF2 results support the MCED test’s use for population-scale screening.
Clinical trial identification
NCT05155605.
Editorial acknowledgement
Medical writing support for the development of this abstract, under the direction of the authors, was provided by Jennifer Hepker, PhD, and Alexandra L. Thomas, PhD, of Citrus Health Group (Chicago, IL, USA), and was funded by GRAIL, Inc.
An interview with: Xiuning Le MD PhD, Medical Oncologist, Department of Thoracic Medicine, UT MD Anderson Cancer Center, Houston TX
BERLIN, Germany—Mutations in the HER2 molecule can be found in a few per cent of non-small cell lung cancers, and these can now be targeted by the new drug sevabertinib that can bring benefit to patients who have the mutation. That’s according to findings from the SOHO-01 study reported at the 2025 Annual Congress of the European Society of Clinical Oncology.
After her talk at the congress, first author Xiuning Le MD PhD, who is a medical oncologist in the Department of Thoracic Medicine, at the University of Texas MD Anderson Cancer Center, in Houston, talked about the new data with Audio Journal of Oncology reporter Peter Goodwin:
Audio Journal of Oncology; Xiuning Le MD PhD
IN: “[GOODWIN] I am at the European Society for Medical ….OUT: ……. For the Audio Journal of Oncology, I’m Peter Goodwin” 10: 18secs
2025 ESMO Berlin ABSTRACT LBA75:
Sevabertinib (BAY 2927088) in advanced HER2-mutant non-small cell lung cancer (NSCLC): Results from the SOHO-01 study
Speaker: Xiuning Le (Houston, United States of America)
Authors: Xiuning Le (Houston, United States of America) Tae Min Kim (Seoul, Republic of Korea) Xiaorong Dong (Wuhan, China) Herbert Ho Fung Loong (Hong Kong, Hong Kong SAR, China) Nicolas Girard (Paris, France) Shun Lu (Shanghai, China) Hye Ryun Kim (Seoul, Republic of Korea) Boon-Cher Goh (Singapore, Singapore) Arsela Prelaj (Milan, Italy) Yong Fang (Hangzhou, China) Lin Wu (Changsha, China) Yuki Shinno (Tokyo, Japan) Gennaro Daniele (Rome, Italy) Tsung-Ying Yang (Taichung City, Taiwan) Gerrina Ruiter (Amsterdam, Netherlands) Jun Zhao (Beijing, China) Jan Christoph Brase (Basel, Switzerland) Rui Li (Whippany, United States of America) Paolo Grassi (Milan, Italy) Lin Li (Beijing, China)
Background
Sevabertinib is a potent, reversible, oral HER2 tyrosine kinase inhibitor with FDA Breakthrough Therapy Designation and Priority Review for pretreated patients (pts) with advanced HER2-mutant NSCLC. We report updated efficacy and safety in pretreated and treatment-naïve pts with HER2-mutant NSCLC in the open-label, multicenter Phase I/II SOHO-01 study.
Methods
Pts with HER2-mutant NSCLC were treated with sevabertinib 20 mg twice daily in 3 cohorts: Cohort D, previous systemic therapy but naïve to HER2 ex20ins-targeted therapy; Cohort E, previous HER2-targeted antibody-drug conjugates; Cohort F, naïve to systemic anti-cancer therapy for advanced disease. The primary endpoint was objective response rate (ORR) by RECIST v1.1 and blinded independent central review. Secondary endpoints were duration of response (DoR) and progression-free survival (PFS).
Results
At the data cut-off (June 27, 2025), 209 pts with HER2-mutant NSCLC were treated: 81 (D), 55 (E), and 73 (F). ORR (95% CI) was 64% (53, 75; D), 38% (25, 52; E), and 71% (59, 81; F). Median (95% CI) DoR was 9.2 (6.3, 13.5; D), 8.5 (5.6, 16.4; E), and 11.0 (8.1, not evaluable; F) months; 12-month DoR rates (95% CI) were 42% (27, 57; D) and 29% (5, 53; E). Median PFS (95% CI) was 8.3 (6.9, 12.3; D) and 5.5 (4.3, 8.3; E) months, and not reached (F). In Cohort D, pts with baseline brain metastases had a similar ORR to those without (61% vs 65%). Among pts with HER2 tyrosine kinase domain (TKD) mutations, those with Y772_A775dupYVMA had a higher ORR (78% vs 57%) and median PFS (12.2 vs 7.0 months) than those with other HER2 TKD mutations. Overall, grade ≥3 treatment-related adverse events (TRAEs) were reported in 31% of pts. Diarrhea was the most commonly reported TRAE, mostly grade 1/2 (grade 3: 14%). TRAEs led to treatment discontinuation in 3% of pts; none due to diarrhea. There were no reports of interstitial lung disease or pneumonitis.
Conclusions
Sevabertinib showed rapid and durable responses with a manageable safety profile in pretreated and treatment-naïve pts with advanced HER2-mutant NSCLC. These data support sevabertinib as a potential practice-changing, new targeted therapy for pts with HER2-mutant NSCLC.
Clinical trial identification: NCT05099172, March 28, 2025.
Editorial acknowledgement: Alice Xue, MSc, Erica Sedgwick, MSc, and Rachel Fairbanks, BA, of Caudex, IPG Health Medical Communications, provided medical writing and editorial assistance in the development of this abstract, funded by Bayer AG.
Legal entity responsible for the study: Bayer AG.
New England Journal of Medicine
https://www.nejm.org/doi/full/10.1056/NEJMoa2511065
An interview with: Christof Vulsteke MD PhD, Medical Oncologist, Head of the Integrated Cancer Center Ghent, Belgium
BERLIN, Germany—Patients with muscle invasive bladder who were ineligible for cisplatin chemotherapy gained large, clinically meaningful and statistically significant benefits from treatment with the antibody drug conjugate enfortumab vedotin combined with pembrolizumab checkpoint inhibition in the phase three KEYNOTE-905 study.
At the 2025 Annual Congress of the European Society for Medical Oncology (ESMO) Medical Oncologist Christof Vulsteke, Head of the Integrated Cancer Centre in Ghent, Belgium, reported marked improvements of event-free and overall survival among patients treated with the new combination, in comparison with those receiving standard radical cystectomy plus pelvic lymph node dissection. After his talk in Berlin he gave more details to Audio Journal of Oncology reporter Peter Goodwin:
Audio Journal of Oncology: Christof Vulsteke MD PhD; IN: “[GOODWIN] I am at the ESMO meeting in Berlin ……OUT: …Goodwin for the Audio Journal of Oncology, Goodbye 7:12 secs
ESMO 2025 ABSTRACT No. LBA2
“Perioperative (periop) enfortumab vedotin (EV) plus pembrolizumab (pembro) in participants (pts) with muscle-invasive bladder cancer (MIBC) who are cisplatin-ineligible: The phase III KEYNOTE-905 study”
Speaker: Christof Vulsteke (Gent, Belgium)
Authors:
Christof Vulsteke (Gent, Belgium) Hristos Kaimakliotis (Indianapolis, United States of America) Pongwut Danchaivijitr (Bangkok, Thailand) Maksym Y. Sabadash (Lviv, Ukraine) Alejo Rodriguez-Vida (Barcelona, Spain) Zhentao Zhang (Fort Wayne, United States of America) Vagiz Atduev (Nizhny Novgorod, Russian Federation) Yunus Emre Goger (Konya, Türkiye) Steffen Rausch (Tuebingen, Germany) Seok Ho Kang (Seoul, Republic of Korea) Yohann Loriot (Villejuif, France) Jens Bedke (Stuttgart, Germany) Matthew D. Galsky (New York, United States of America) Peter H. O’Donnell (Chicago, United States of America) Michael Mihm (Chicago, United States of America) Changting Meng (Groton, United States of America) David Huang (Rahway, United States of America) Chethan Ramamurthy (North Wales, United States of America) Blanca Homet Moreno (Madrid, Spain) Anders Ullén (Stockholm, Sweden)
Background
Radical cystectomy + pelvic lymph node dissection (RC + PLND) is the standard treatment for pts with MIBC who are cisplatin-ineligible. Periop therapy may improve outcomes in these pts.
Methods
The phase 3 KEYNOTE-905/EV-303 study (NCT03924895) evaluated efficacy and safety of periop EV + pembro and RC + PLND vs RC + PLND in adult pts with MIBC (T2-T4aN0M0 or T1-T4aN1M0) who were cisplatin-ineligible or declined cisplatin. Pts were randomized 1:1 to EV + pembro (3 cycles EV 1.25 mg/kg on d1 and d8 + pembro 200 mg on d1 Q3W, followed by RC + PLND, then 6 cycles EV + 14 cycles pembro) vs control (RC + PLND only). Study therapy continued until progression, unacceptable adverse events (AEs), withdrawal of consent, or completion of planned treatment. The primary endpoint was event-free survival (EFS) by blinded independent central review. Secondary endpoints were overall survival (OS; key), pathological complete response (pCR) rate (key), and safety.
Results
170 pts were randomized to EV + pembro and 174 pts to control. >80% of pts were cisplatin-ineligible per Galsky criteria. As of Jun 6, 2025, median follow-up time was 25.6 mo (range, 11.8–53.7). 149 pts (87.6%) in the EV + pembro arm and 156 (89.7%) in the control underwent surgery. EV + pembro significantly improved EFS (median not reached [NR] vs 15.7 mo; HR 0.40; 95% CI 0.28–0.57; P<.001), OS (NR vs 41.7 mo; HR 0.50; 95% CI 0.33–0.74; P<.001), and pCR rate (57.1% vs 8.6%; estimated difference 48.3%; 95% CI 39.5–56.5; P<.001) vs control. Treatment-emergent AEs occurred in 100% (gr ≥3, 71.3%) of pts in the EV + pembro arm and 64.8% (gr ≥3, 45.9%) in the control. Most frequent gr ≥3 AE of special interest (based on distinct prespecified lists for each drug) was severe skin reactions (grouped term; 11.4%) for pembro, and skin reactions (grouped term; 10.8%) for EV.
Conclusions
Adding periop EV + pembro to surgery significantly and meaningfully improved EFS, OS, and pCR rate in pts with MIBC who were predominantly cisplatin-ineligible. The safety profile of EV + pembro was manageable and consistent with prior reports. This is the first perioperakthrough regimen to improve outcomes vs RC + PLND in this setting and may be a new standard of care.
Clinical trial identification: NCT03924895.
An interview with: Xichun Hu MD PhD, Professor, Director, Department of Medical Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China
BERLIN, Germany—In a head-to-head comparison of two antibody drug conjugates used to treat unresectable or metastatic breast cancer, patients treated with trastuzumab botidotin lived more than twice as long before disease progression than those in the control arm receiving trastuzumab emtansine (T-DM1). This finding was announced by Chinese researchers at the 2025 Annual Congress of the European Society of Medical Oncology.
Lead author Xichun Hu MD PhD, Professor, Director, Department of Medical Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China talked about the findings of his groups phase three randomized controlled study with Audio Journal of Oncology reporter Peter Goodwin:
AUDIO JOURNAL OF ONCOLOGY: Xichun Hu MD PhD
IN: “[GOODWIN] Peter Goodwin at ESMO ..OUT: ..of Oncology, I’m Peter Goodwin 8:30 sec
ESMO ABSTRACT LBA24
“Trastuzumab botidotin vs trastuzumab emtansine (T-DM1) in HER2-positive unresectable or metastatic breast cancer: Results from a randomized phase III study”
Speaker: Xichun Hu (Shanghai, China)
Authors:
Xichun Hu (Shanghai, China) Jian Zhang (Shanghai, China) Quchang Ouyang (Changsha, China) Qingyuan Zhang (Harbin, China) Huihui Li (Jinan, China) Xu Wang (Tianjin, China) Ying Wang (Guangzhou, China) Yongmei Yin (Nanjing, China) Shusen Wang (Guangzhou, China) Yuanting Gu (Zhengzhou, Algeria) Tao Sun (Shenyang, China) Jingfen Wang (Linyi, China) Xinhong Wu (Wuhan, China) Fanfan Li (Hefei, China) Xi Chen (Fuzhou, China) Man Li (Dalian, China) Jin Yang (Xi’an, Shaanxi Province, China) Hua Yang (Baoding, China) Xiaoping Jin (Chengdu, China) Junyou Ge (CHENGDU, China)
Lecture Time
ASTRACT
Background
Trastuzumab botidotin (A166) is a HER2-directed ADC developed using a stable, protease-cleavable valine-citrulline linker conjugated to the anti-microtubule agent Duo-5. In a phase 1 study, A166 showed promising activity in heavily pretreated patients (pts) with HER2+ breast cancer (BC). Here, we first report the results from a phase 3 study (NCT06968585).
Methods
Pts with HER2+ unresectable or metastatic BC who had received at least one prior anti-HER2 therapy were randomized (1:1) to receive A166 (4.8 mg/kg Q3W) or T-DM1 (3.6 mg/kg Q3W) until disease progression or unacceptable toxicity. The primary endpoint was PFS by BICR per RECIST v1.1.
Results
A total of 365 pts were randomized (median age 55 years; 73.4% with visceral metastases; 53.4% received ≥2 prior anti-HER2 therapies; 55.9% had prior pyrotinib). As of 26 April 2025, median follow-up was 14.9 mo. Median PFS was significantly longer in A166 than in T-DM1 (11.1 mo vs 4.4 mo; HR 0.39 [95% CI 0.30-0.51], p<0.0001). PFS benefit with A166 was consistently observed regardless of prior lines of anti-HER2 therapy (HR 0.36 for 1 prior line; HR 0.39 for ≥2 prior lines). ORR by BICR was 76.9% vs 53.0%, and mDOR was 12.2 mo vs 5.7 mo. Although OS data were immature, a trend toward benefit was observed in A166 (HR 0.62; 95% CI, 0.38-1.03). Grade ≥3 TEAEs occurred in 69.8% of pts in A166 and 63.7% in T-DM1. The most common grade ≥3 TEAEs (≥5%) were corneal disorder, dry eye, and vision blurred in A166, and platelet count decreased, neutrophil count decreased, hypokalemia, and GGT increased in T-DM1. Among A166-treated pts who experienced any-grade ocular AEs, instrumental activities of daily living (ADL) limitations occurred in 37 (20.3%) pts, and self-care ADL limitations in 13 (7.1%) pts; these resolved in 32 (86.5%) and 12 (92.3%) pts, respectively. TEAEs led to discontinuation in 1.1% of pts in A166 and 3.8% in T-DM1. No TEAE led to death in A166, compared with 1.1% in T-DM1.
Conclusions
A166 demonstrated statistically significant and clinically meaningful improvement in PFS compared with T-DM1, with a manageable safety profile in pts with HER2+ unresectable or metastatic BC. These results position A166 as a potential new therapeutic option for HER2+ disease.
Clinical trial identification
NCT06968585.
Legal entity responsible for the study
Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd.
Funding
Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd.
Disclosure
- Jin, J. Ge: Financial Interests, Institutional, Full or part-time Employment: Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. All other authors have declared no conflicts of interest.
Xichun Hu MD, PhD
Medical Oncology
Xuhui, Shanghai, China
Xi-Chun Hu, M.D., Ph. D., is currently a Professor, Director of the Department of Medical Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China. Dr. Hu has published more than 170 papers in the journals, such as Lancet Oncology, JCO, and International Journal Cancer, and 5 book chapters. He is vice editor of the ABC (Advanced breast cancer) guideline (Chinese version) and one of the leading authors of the CBCS (Chinese Breast Cancer Society) guideline for breast cancer diagnosis and treatment which is updated biannually.
Dr. Hu is an active member of the American Society of Clinical Oncology, General secretary & Member of the standing committee of CBCS (Chinese Breast Cancer Society), Vice-chair of Shanghai Breast Cancer Society, Member of the Standing Academic Committee of CSCO (Chinese Society of Clinical Oncology).
Dr. Hu’s major interest is in the diagnosis and management of breast cancer, both in the clinic and in the laboratory, and in phase I trial on new anticancer agents. His laboratory interests and contributions have been in the area of serum tumor markers, epigenetic alteration and gene expression, and detection of residual disease. He and his laboratory are now concentrating on translational research on triple-negative breast cancer and angiogenesis.
An interview with: Martin Wermke MD, TU Dresden, NCT/UCC Early Clinical Trial Unit and Medical Clinic, Poliklinik I, Natural Centre for Tumor Diseases, Dresden, Germany
BERLIN, Germany—The prospect of markedly better outcomes for patients with small cell lung cancer, with “encouraging initial survival outcomes”, was raised by findings from the DeLLphi-303 study, reported at the European Society for Medical Oncology (ESMO) 2025 Annual Congress. The bi-specific T-cell engager drug tarlatamab was included with initial therapy for patients with extensive stage small cell lung cancer.
Martin Wermke MD, from TU Dresden, Director of the NCT/UCC Early Clinical Trial Unit and of the Medical Clinic, Poliklinik I, Natural Centre for Tumor Diseases in Dresden, Germany reported the latest study data to the ESMO congress. After his talk he gave the details to our reporter Peter Goodwin:
Audio Journal of Oncology; Martin Wermke MD: ”[GOODWIN] Peter Goodwin here at the ESMO meeting ………….of Oncology, I’m Peter Goodwin.” 6:16secs
https://pubmed.ncbi.nlm.nih.gov/40934933/
ESMO ABSTRACT 2757O
Tarlatamab with first-line chemoimmunotherapy for extensive stage small cell lung cancer (ES-SCLC): DeLLphi-303 study
Speaker: Martin Wermke (Dresden, Germany)
Authors
Martin Wermke (Dresden, Germany) Sally Lau (Toronto, Canada) Mor T. Moskovitz (Petah Tikva, Israel) Ingel Demedts (Roeselare, Belgium) Kelly Paulson (Seattle, United States of America) Aurélie Swalduz (Lyon, France) Cornelius Waller (Freiburg, Germany) Luis Paz-Ares (Madrid, Spain) Makoto Nishio (Koto-ku, Japan) Michael Boyer (Camperdown, Australia, NSW) James Chih-Hsin Yang (Taipei City, Taiwan) Amanda Parkes (Thousand Oaks, United States of America) Yuyang Zhang (Thousand Oaks, United States of America) Ali Hamidi (Thousand Oaks, United States of America) Mukul Minocha (Thousand Oaks, United States of America) Pedro F. Simoes da Rocha (Barcelona, Spain)
Background: Tarlatamab with anti-PD-L1 achieved notable survival outcomes with manageable safety as maintenance therapy following 1L platinum-etoposide chemotherapy and anti-PD-L1 (1L chemo-IO) for ES-SCLC. In this phase Ib study (parts 2, 4, 7), the safety and efficacy of adding tarlatamab to 1L chemo-IO was assessed.
Methods: Patients (pts) had received 1 cycle of 1L chemo-IO prior to enrollment. On study, pts received 3 cycles of tarlatamab + 1L chemo-IO followed by tarlatamab + anti-PD-L1 Q3W until progression. Tarlatamab was administered 20 mg Q3W with a 1 mg step dose. Primary endpoints included dose-limiting toxicities (DLTs), treatment-emergent (TE), and treatment-related (TR) adverse events (AEs). Key secondary endpoints were objective response (OR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
Results: Of 96 pts enrolled, 3 (3%) had DLTs. TEAEs and TRAEs were reported in all pts. The most common TRAEs were cytokine release syndrome (CRS, 56%), anemia (54%), and dysgeusia (46%). Grade (Gr) ≥ 3 TRAEs occurred in 72 pts (75%), most commonly neutropenia/neutrophil count decreased (44%), anemia (23%), and lymphopenia/lymphocyte count decreased (11%), primarily within the first two cycles. CRS (54% Gr 1-2; 2% Gr 3-4) and ICANS and associated neurological events (5% Gr 1-2; 1% Gr 3) TRAEs were mostly low grade. Other immune-related AEs were rare (2%). From a baseline scan after 1 cycle of 1L chemo-IO, OR rate following tarlatamab addition to 1L chemo-IO was 71%, with median DOR of 11.0 months (mo) (95% CI 6.7-not estimable). Median PFS was 9.0 mo. With a median follow-up time of 11.3 mo, the Kaplan-Meier estimate of OS at 12 mo was 81% (Table). Results from further follow-up will be presented. Table: 2757O
Safety and efficacy of tarlatamab + chemoimmunotherapy as 1L treatment for ES-SCLC
Conclusions: The combination of tarlatamab with chemo-IO for 1L treatment of ES-SCLC demonstrated manageable safety with encouraging initial survival outcomes, supporting further investigation of this combination in the phase III DeLLphi-312 study.
Clinical trial identification: NCT05361395.
Editorial acknowledgement
Medical writing support for the development of this abstract was provided by Sukanya Raghuraman, PhD, of Cactus Life Sciences, part of Cactus Communications, and Liz Leight, PhD, an employee of Amgen Inc., and was funded by Amgen Inc.
Legal entity responsible for the study: Amgen Inc.
Funding: Amgen Inc.
An interview with: John P. Crown MD MBA, Consultant Medical Oncologist, St. Vincent’s University Hospital, Dublin, Professor of Translational Cancer Research, Dublin City University, Professor of Medicine, University College Dublin Ireland.
BERLIN, Germany—Patients with high-risk node-negative ER-positive HER2-negative early breast cancer who had the CDK 4/6 inhibitor drug ribociclib added to their non-steroidal aromatase inhibitor (AI) adjuvant therapy after surgery had significantly longer freedom from progression to invasive disease compared with patients receiving the AI alone. This is according to five-year data from the NATALEE trial reported at the 2025 Annual Congress of the European Society for Medical Oncology.
Professor John P. Crown MD MBA, Consultant Medical Oncologist, from St. Vincent’s University Hospital in Dublin gave reporter Peter Goodwin the latest details:
Audio Journal of Oncology, John P. Crown MD MBA,
IN: “[GOODWIN] I am at the ESMO meeting, 2025, in Berlin ….OUT: signing off for the Audio Journal of Oncology.” 11:24 secs
2025 ESMO: Proffered Paper Friday 14:00 Oct 17, 2025
Abstract Title:
LBA14 – Adjuvant ribociclib (RIB) plus nonsteroidal aromatase inhibitor (NSAI) in patients (pts) with HR+/HER2− early breast cancer (EBC): NATALEE 5-year outcomes
Speaker:
John P. Crown (Dublin, Ireland)
Authors:
John P. Crown (Dublin, Ireland) Daniil Stroyakovskiy (Moscow, Russian Federation) Denise Yardley (Chattanooga, United States of America) Chiun-Sheng Huang (Taipei City, Taiwan) Peter A. Fasching (Erlangen, Germany) Aditya Bardia (Los Angeles, United States of America) Stephen Chia (Vancouver, Canada) Seock-Ah Im (Seoul, Republic of Korea) Miguel Martin (Madrid, Spain) Binghe Xu (Beijing, China) Carlos H. Barrios (Porto Alegre, Brazil) Michael Untch (Berlin, Germany) Rebecca Moroose (Lake Mary, United States of America) Sara A. Hurvitz (Seattle, United States of America, CA) Gabriel N. Hortobagyi (Houston, United States of America) Dennis Slamon (Los Angeles, United States of America) Frances Visco (Washington, United States of America) Gonzalo Spera (Montevideo, Uruguay) Zheng Li (East Hanover, United States of America) Sherene Loi (Melbourne, Australia, VIC)
Background:
The phase 3 NATALEE trial demonstrated that adjuvant RIB + NSAI led to a statistically significant invasive disease–free survival (iDFS) benefit in pts with stage II and III HR+/HER2− EBC. We present a protocol-specified 5-year efficacy analysis.
Methods:
Pts with HR+/HER2− EBC were randomized 1:1 to RIB (400 mg/d; 3 weeks on/1 week off for 3 y) + NSAI (letrozole 2.5 mg/d or anastrozole 1 mg/d for 5 y) or NSAI alone. Men and premenopausal women received goserelin. Pts were included if they had anatomical stage IIA (if N1 [1-3 axillary lymph nodes] or N0 with additional high-risk factors), stage IIB, or stage III disease per AJCC, 8th ed. The primary end point of iDFS and secondary efficacy end points of distant disease–free survival (DDFS), distant relapse–free survival (DRFS), and overall survival (OS) were evaluated using Kaplan-Meier methods. Statistical comparisons were made by stratified log-rank test.
Results:
At data cutoff (May 28, 2025), all pts were off RIB treatment, and a similar proportion had completed 5 years of NSAI treatment in both arms (RIB + NSAI, 36.5%; NSAI alone, 34.4%). With a median iDFS follow-up of 55.4 months, RIB + NSAI demonstrated persistent iDFS benefit over NSAI alone (hazard ratio [HR], 0.716; 95% CI: 0.618-0.829; nominal 1-sided P<.0001). Absolute iDFS rates were 90.8% vs 88.0% at 3 y, 88.3% vs 83.9% at 4 y, and 85.5% vs 81.0% at 5 y (absolute improvement of 2.7%, 4.4%, and 4.5%, respectively). iDFS benefit was observed across subgroups, including N0 (HR, 0.606; 95% CI: 0.372-0.986). RIB + NSAI also demonstrated continued DDFS (HR, 0.709; 95% CI: 0.608-0.827) and DRFS (HR, 0.699; 95% CI: 0.594-0.824) benefit vs NSAI alone. A positive trend for OS favoring RIB + NSAI (HR, 0.800; 95% CI: 0.637-1.003; nominal 1-sided P=.026) continues to emerge. No new safety signals were observed with a median follow-up time of approximately 2 years after RIB completion.
Conclusions:
In this 5-year landmark analysis with mature efficacy data, RIB + NSAI reduced the risk of invasive and distant disease recurrence compared with NSAI alone, including in pts with high-risk N0 disease. A positive trend for OS in favor of RIB + NSAI continues to emerge.
An interview with: Javier C Cortés MD PhD, Breast Cancer Medical Oncologist, IOB Madrid, Institute of Oncology, Madrid, and International Breast Cancer Centre, Barcelona, Spain
BERLIN, Germany—Treatment with the antibody drug conjugate (ADC) sacituzumab govitecan (that targets the Trop-2 cancer-associated protein, delivering a cytotoxic topoisomerase inhibitor payload) has significantly improved progression-free survival in patients with newly-diagnosed metastatic triple-negative breast cancer who were not candidates for treatment with immune checkpoint inhibition and had received no prior therapy.
At the European Society for Medical Oncology (ESMO) 2025 Annual Congress Javier C Cortés MD PhD from the Institute of Oncology in Madrid and the International Breast Cancer Centre in Barcelona reported data from the ASCENT-03 study showing that treatment with sacituzumab govitecan brought clinically meaningful benefits with toxicities that were found to be manageable.
At the congress Cortés talked about the new findings with Peter Goodwin:
Audio Journal of Oncology: Javier C Cortes MD PhD
“[GOODWIN] Peter Goodwin here in Berlin …..……….Audio Journal of Oncology, I’m Peter Goodwin. 9:47secs
ESMO ABSTRACT:
LBA20 – “Primary results from ASCENT-03: A randomized phase III study of sacituzumab govitecan (SG) vs chemotherapy (chemo) in patients (pts) with previously untreated advanced triple-negative breast cancer (TNBC) who are unable to receive PD-(L)1 inhibitors (PD-[L]1i)”
Speaker: Javier C. Cortés (Barcelona, Spain)
Authors: Javier C. Cortés (Barcelona, Spain), Aditya Bardia (Los Angeles, United States of America), Kevin Punie (Antwerp, Belgium), Carlos H. Barrios (Porto Alegre, Brazil), Sara A. Hurvitz (Seattle, United States of America, CA),Andreas Schneeweiss (Heidelberg, Germany), Joohyuk Sohn (Seoul, Republic of Korea), Eriko Tokunaga (Fukuoka, Japan), Adam M. Brufsky (Pittsburgh, United States of America, PA), Yeon Hee Park (Seoul, Republic of Korea), Binghe Xu (Beijing, China), Roberto Hegg (São Paulo, Brazil), Mafalda Oliveira (Barcelona, Spain), Alessandra Fabi (Rome, Italy), Natalya Vaksman (Miami, United States of America), Theresa Valdez (Miami, United States of America), Xinrui Zhang (Miami, United States of America), Catherine Lai (Foster City, United States of America, CA), Sara M. Tolaney (Boston, United States of America, MA)
Background
Significant PFS benefit was observed with SG vs chemo in pretreated metastatic (m)TNBC (ASCENT) and with SG + pembrolizumab vs chemo + pembrolizumab in first-line (1L) PD-L1+ mTNBC (ASCENT-04). For pts with mTNBC who cannot receive PD-(L)1i, treatment options are limited. We report primary results from the randomized phase 3 ASCENT-03 study (NCT05382299) of 1L SG vs chemo in pts with locally advanced unresectable or mTNBC who are unable to receive a PD-(L)1i.
Methods
Pts had centrally confirmed PD-L1− mTNBC (defined as combined positive score [CPS] < 10) or PD-L1+ mTNBC (CPS ≥ 10) but were unable to receive PD-(L)1i due to a comorbidity or prior use in the curative setting. Randomization (1:1) to SG (10 mg/kg IV, days 1 & 8 in 21-day cycles) or chemo (paclitaxel, nab-paclitaxel, or gemcitabine + carboplatin) was stratified by disease status and geography. The primary end point was PFS by BICR. Key secondary end points included overall survival (OS), ORR and DOR by BICR, and safety.
Results
558 pts (279 in each group) with mTNBC were randomized. With a median follow-up of 13.2 mo, SG showed a significant improvement in median PFS vs chemo (9.7 vs 6.9 mo; HR, 0.62; 95% CI, 0.50-0.78; P < .0001); median DOR was 12.2 mo vs 7.2 mo (Table). OS data were immature. The most frequent grade ≥ 3 TEAEs were neutropenia (43%) and diarrhea (9%) with SG and neutropenia (41%) and anemia (16%) with chemo.
Conclusions
SG led to a statistically significant and clinically meaningful improvement in PFS and more durable responses vs chemo in 1L mTNBC. The safety profile of SG was manageable and consistent with its known profile; treatment discontinuation rate due to TEAEs was lower with SG vs chemo. These data support SG as a potential new standard of care for pts with previously untreated mTNBC who are unable to receive a PD-(L)1i. Table: LBA20
Clinical trial identification
NCT05382299.
Editorial acknowledgement
Editorial assistance was provided by Peggy Robinet, PharmD, PhD, and Sonal S. Joshi, PhD, of Parexel, and funded by Gilead Sciences, Inc.
Legal entity responsible for the study
Gilead Sciences, Inc.
Funding
Gilead Sciences, Inc.
PRESS RELEASE:
ASCENT-03: Trodelvy® Demonstrates Highly Statistically Significant & Clinically Meaningful Improvement in Progression Free Survival in Patients With First-line Metastatic Triple-Negative Breast Cancer Who Are Not Candidates for Checkpoint Inhibitors
– Second Positive Phase 3 Trial in First-line Metastatic TNBC Where Trodelvy Has Demonstrated a Clinically Meaningful Benefit Versus Standard of Care Chemotherapy –
– Trodelvy Has the Potential to Be the Backbone of Treatment and the First Antibody-Drug Conjugate for All Patients Across First-line Metastatic TNBC –
FOSTER CITY, Calif.–(BUSINESS WIRE)– Gilead Sciences, Inc. (Nasdaq: GILD) today announced positive topline results from the Phase 3 ASCENT-03 study of Trodelvy® (sacituzumab govitecan-hziy). The study met its primary endpoint, demonstrating a highly statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to chemotherapy in patients with first-line metastatic triple-negative breast cancer (mTNBC) who are not candidates for PD-1/PD-L1 inhibitors, meaning they are PD-L1 negative or are ineligible to receive immunotherapy.
“Almost half of the patients diagnosed with metastatic triple-negative breast cancer do not receive treatment beyond first-line, demonstrating an urgent need for innovative treatment options in this early setting,” said Dr. Javier Cortes, Head of the International Breast Cancer Center in Spain and principal investigator of the ASCENT-03 study. “Traditional chemotherapy has been the standard of care for early treatment of metastatic triple-negative breast cancer, and we know that therapeutic advances in this disease area serve a critical unmet need for patients and the broader oncology community.”
Together with the recently announced positive results from the ASCENT-04 study evaluating Trodelvy plus Keytruda® in patients with previously untreated PD-L1+ metastatic TNBC, Trodelvy now has the potential to be the backbone treatment for all patients across first-line mTNBC. Detailed data from the ASCENT-04 study will be shared during the American Society of Clinical Oncology (ASCO) meeting taking place May 30 – June 3, 2025.
“The ASCENT-03 outcome represents the first clinically meaningful advance for this patient population in over 20 years versus chemotherapy,” said Dietmar Berger, MD, PhD, Chief Medical Officer, Gilead Sciences. “By addressing this aggressive and difficult to treat disease earlier, we can potentially improve treatment options for the high unmet need that patients with metastatic triple-negative breast cancer face.”
The safety profile of Trodelvy in the ASCENT-03 study was consistent with prior studies, and no new safety signals were identified in this patient population. Overall survival (OS) is a key secondary endpoint and was not mature at the time of PFS primary analysis. No OS detriment was observed. Gilead will continue to monitor OS outcomes, with ongoing patient follow-up and further analysis planned.
Detailed results from the ASCENT-03 study will be presented at a future medical meeting and discussed with regulatory authorities. The use of Trodelvy in first-line mTNBC is investigational, and the safety and efficacy of this use have not been established.
Healthcare professionals have well-established experience with Trodelvy, which has shown generally consistent outcomes across both clinical trials and real-world studies in 60,000+ patients across 50+ countries over approximately five years. It is the only antibody-drug conjugate (ADC) with four positive Phase 3 trials in HER2- (IHC 0, IHC 1+ or IHC 2+/ISH–) metastatic breast cancer (mBC), and remains the only approved Trop-2-directed ADC that has demonstrated meaningful survival advantages in two different types of metastatic breast cancers: 2L mTNBC and pre-treated HR+/HER2- mBC.
Trodelvy is a Category 1 preferred treatment for both currently approved indications per the National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology (NCCN Guidelinesi) and the only ADC with an ESMO Magnitude of Clinical Benefit Scale (MCBS) rating of 5 for mTNBC. Trodelvy also has an MCBS rating of 4 for women with HR+/HER2- mBC.
Currently, Gilead has additional ongoing Phase 3 studies investigating Trodelvy across HER2- (IHC 0, IHC 1+ or IHC 2+/ISH–) breast cancer including the ASCENT-07 pivotal trial in patients with HR+/HER2- mBC who have received endocrine therapy, and the ASCENT-05 pivotal trial in patients with early-stage TNBC (eTNBC). Trodelvy is also being evaluated in additional Phase 3 studies across a range of tumor types, including in lung and gynecologic cancers.
Gilead would like to thank the patients, families, investigators and advocates who have contributed and continue to contribute to this important research. We remain committed to advancing care to address the unmet needs for the breast cancer community.
KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
About Triple-Negative Breast Cancer (In Patients Who Are Not Candidates for PD-1/PD-L1 inhibitors)
Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer and has historically been difficult to treat, accounting for approximately 15% of all breast cancers. TNBC disproportionately impacts younger, pre-menopausal as well as Black and Hispanic women. TNBC cells do not have estrogen and progesterone receptors and have limited HER2. Due to the nature of TNBC, treatment options are extremely limited compared with other breast cancer types. TNBC has a higher chance of recurrence and metastases than other breast cancer types. The average time to metastatic recurrence for TNBC is approximately 2.6 years compared with 5 years for other breast cancers, and the relative five-year survival rate is much lower. Among women with metastatic TNBC, the five-year survival rate is 12%, compared with 28% for those with other types of mBC.
Chemotherapy remains the mainstay of treatment in first-line mTNBC patients who are not candidates for PD-1/PD-L1 inhibitors, and the need to improve outcomes continues to be high. In mTNBC overall, ~50% of patients do not receive treatment beyond 1L setting, demonstrating a need for additional effective earlier-line treatment options.
About the ASCENT-03 Study
The ASCENT-03 study is a global, open-label, randomized Phase 3 trial evaluating the efficacy and safety of sacituzumab govitecan compared with treatment of physician’s choice in patients with previously untreated, locally advanced, inoperable, or metastatic triple-negative breast cancer (mTNBC) whose tumors do not express PD-L1, or who are PD-L1 positive and previously treated with a PD-(L)1 inhibitor in the curative setting. ~540 patients were enrolled across multiple study sites worldwide.
Patients were randomized 1:1 to receive either sacituzumab govitecan (10 mg/kg intravenously on Days 1 and 8 of a 21-day cycle) or treatment of physician’s choice, which included gemcitabine plus carboplatin, paclitaxel, or nab-paclitaxel. Treatment continued until blinded independent central review (BICR)-verified disease progression or unacceptable toxicity. Patients randomized to chemotherapy were eligible to crossover to sacituzumab govitecan upon disease progression.
The primary endpoint of the study is progression-free survival (PFS) as assessed by BICR according to RECIST v1.1. Secondary endpoints include overall survival (OS), objective response rate (ORR), duration of response (DOR), time to onset of response (TTR), patient-reported outcomes (PROs), and safety.
More information about ASCENT-03 is available at ClinicalTrials.gov: NCT05382299.
About Trodelvy
Trodelvy® (sacituzumab govitecan-hziy) is a first-in-class Trop-2-directed antibody-drug conjugate. Trop-2 is a cell surface antigen highly expressed in multiple tumor types, including in more than 90% of breast and lung cancers. Trodelvy is intentionally designed with a proprietary hydrolyzable linker attached to SN-38, a topoisomerase I inhibitor payload. This unique combination delivers potent activity to both Trop-2 expressing cells and the tumor microenvironment through a bystander effect.
Trodelvy is currently approved in more than 50 countries for second-line or later metastatic triple-negative breast cancer (TNBC) patients and in more than 40 countries for certain patients with pre-treated HR+/HER2- metastatic breast cancer.
Trodelvy is currently being evaluated in multiple ongoing Phase 3 trials across a range of tumor types with high Trop-2 expression. These studies with Trodelvy, both in monotherapy and in combination with pembrolizumab, involve earlier lines of treatment for TNBC and HR+/HER2- breast cancer—including in curative settings—as well as in lung and gynecologic cancers, where previous proof-of-concept studies have demonstrated clinical activity.
INDICATIONS
TRODELVY® (sacituzumab govitecan-hziy) is a Trop-2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:
Unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease.
Unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+ or IHC 2+/ISH–) breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting.
An interview with:
Trevor Leong MD, Peter McCallum Cancer Centre, Radiation Oncology Department, Melbourne, Australia
BARCELONA, Spain—Although pre-operative radiotherapy brought better response rates in patients resected for their gastric or GE-junction adenocarcinomas, there was no improvement in survival. This is the clear finding from a big, long-term study led by an Australian team.
The multi-continent, phase-three randomized TOP GEAR trial, headquartered in Sydney Australia, definitively found no benefit for overall or progression-free survival from adding radiation before surgery.
This clear finding was announced at the 2024 Annual Meeting of the European Society for Medical Oncology (ESMO), held in Barcelona, Spain
First author Trevor Leong MD, from the Radiation Oncology Department of the Peter McCallum Cancer Centre in Melbourne Australia, talked about the results with Peter Goodwin:
Trevor Leong MD interview (8mins 37 secs):
IN: “Resectable gastric or gastro-esophageal…. OUT: ,,’till next time, Good-bye.”
ESMO 2024, Barcelona, ABSTRACT:
03880-8/fulltext
“A randomised phase three trial of perioperative chemotherapy (CT) with or without pre-operative chemoradiotherapy (CRT) for resectable gastric cancer (AGITG TOPGEAR). Final results from an intergroup trial of AGITG, TROG, EORTC and CCTG”.
NEJM September 13, 2024:
https://www.nejm.org/doi/full/10.1056/NEJMoa2405195
TITLE:
“Preoperative Chemoradiotherapy for Resectable Gastric Cancer”
From: The Australasian Gastro-Intestinal Trials Group, National Health and Medical Research Council Clinical Trials Centre, Trans-Tasman Radiation Oncology Group, European Organisation for Research and Treatment of Cancer, and Canadian Cancer Trials Group.
JOURNAL Article: N Engl. J Med.:
“The addition of preoperative chemoradiotherapy to perioperative chemotherapy did not improve overall survival as compared with perioperative chemotherapy alone among patients with resectable gastric and gastroesophageal junction adenocarcinoma.”
“A randomised phase three trial of perioperative chemotherapy (CT) with or without pre-operative chemoradiotherapy (CRT) for resectable gastric cancer (AGITG TOPGEAR). Final results from an intergroup trial of AGITG, TROG, EORTC and CCTG”.
Background
In Western countries, the current standard of care for resectable gastric cancer is periop CT. There is much interest in preop CRT, but comparison to periop CT alone is lacking. In TOPGEAR we hypothesized that adding preop CRT to periop CT would improve pathological complete response (pCR) rates and ultimately overall survival (OS) compared to periop CT alone.
Methods
This international phase 3 trial randomized patients with resectable adenocarcinoma of the stomach and gastro-esophageal junction to periop CT alone, or with preop CRT. The periop CT alone group received 3 cycles of epirubicin/cisplatin/5-fluorouracil (ECF) or 4 cycles of fluorouracil/leucovorin/oxaliplatin/docetaxel (FLOT) both pre- and post-operatively. The preop CRT group received one less cycle of preop chemotherapy followed by chemoradiotherapy (45 Gy in 25 fractions radiation plus infusional 5-FU ), and then the same postop chemotherapy. The primary endpoint was overall survival, and secondary endpoints included progression free survival (PFS), pCR rates, toxicity and quality of life.
Results
Between September 2009 and May 2021, 574 patients were enrolled from 70 sites across 15 countries in Australasia, Europe, and Canada; 288 to periop CT group and 286 to preop CRT group. Compared to periop CT alone, patients receiving preop CRT achieved a higher pCR rate (16.7% vs 8.0%), a higher rate of major pathological response (0 – <10% residual tumor: 49.5% vs 29.3%), and greater tumor downstaging following resection. After a median follow-up of 66.7 months, there was no significant difference in OS or PFS: median OS periop CT 49.4 months vs preop CRT 46.4 months; median PFS periop CT 31.8 months vs preop CRT 31.4 months. Preop CRT was not associated with increased perioperative treatment toxicity or a higher rate of surgical complications.
Conclusions
Despite improving pathological outcomes, the addition of preop CRT to periop CT does not improve overall survival compared to periop CT alone in patients with resectable gastric and gastro-esophageal junction adenocarcinoma.
Clinical trial identification
ACTRN12609000035224. Registered 30 May 2009; NCT01924819.
Legal entity responsible for the study
Australasian Gastro-Intestinal Trials Group (AGITG).
Funding
This work was supported by grants from the National Health and Medical Research Council: 1046425 and 2000711, Canadian Institutes of Health Research (CIHR) grant no. 119445, the Canadian Cancer Society Research Institute (CCSRI) grant no. 021039, the Health Research Council of New Zealand (HRC) International Investment Opportunities Fund: Contract no. 09/624, the EORTC Cancer Research Fund, and the Cancer Australia Priority-driven Collaborative Research Scheme: Project ID: 570996.
Disclosure
K.M. Haustermans: Financial Interests, Personal, Other, Clinical editor Radiotherapy & Oncology: Elsevier; Financial Interests, Institutional, Funding: IBA; Financial Interests, Institutional, Research Grant: Varian,
https://www.audiomedica.com/wp-content/2025/10/Trevor-Leong-ESMO-AJO-PRODUCTION-MASTER.mp3Editorial acknowledgement
Editorial and medical writing support was provided in accordance with Good Publication Practice guidelines by Lewis Cawkwell, PhD, of Parexel, and was funded by AstraZeneca.
Legal entity responsible for the study
AstraZeneca.
An interview with: Domenica Lorusso MD PhD, Director of the Gynaecological Oncology Unit, full Professor of Obstetrics and Gynaecology, Humanitas Hospital San Pio X, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of the Sacred Heart, Rome, Italy.
Both overall and progression-free survival were significantly improved when the anti-PD-1 agent pembrolizumab was added to standard chemoradiotherapy as initial treatment for patients with high-risk locally advanced cervical cancer.
Results from the randomized, double-blind, phase III KEYNOTE-A18 study of immunotherapy, used together with standard concurrent chemoradiotherapy among 1060 patients, were reported by a multinational team of researchers led from Italy to the 2024 Annual Congress of the European Society for Medical Oncology in Barcelona.
The study lead author Domenica Lorusso MD PhD, Director of the Gynaecological Oncology Unit at Humanitas Hospital San Pio X, in Milan, who is a Full Professor of Obstetrics and Gynaecology at Humanitas University, Rozzano, met up with Peter Goodwin to discuss the KEYNOTE-A18 findings.
Audio Journal of Onclogy: Domenica Lorusso MD PhD IN: “Immune checkpoint inhibition …..OUT: …….in Barcelona at the ESMO meeting”. Durn: 7:20 secs
ESMO Abstract 7090
- Lorusso, Gynaecology Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS and Catholic University of the Sacred Heart, Rome, Italy
“Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer: Overall survival results from the randomized, double-blind, phase III ENGOT-cx11/ GOG-3047/KEYNOTE-A18 study”
Background
At the first interim analysis of the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study (NCT04221945), pembrolizumab (pembro) + concurrent chemoradiotherapy (CCRT) showed a statistically significant and clinically meaningful improvement in PFS vs placebo (pbo) + CCRT in patients (pts) with high-risk locally advanced cervical cancer (LACC). Based on this study, the US FDA has approved pembro + CCRT for pts with FIGO 2014 Stage III-IVA cervical cancer. We present the OS results from the second interim analysis.Methods
Eligible pts with newly diagnosed, previously untreated, high-risk LACC (FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA regardless of lymph node status) were randomized 1:1 to 5 cycles of pembro 200 mg or pbo Q3W + CCRT, then 15 cycles of pembro 400 mg or pbo Q6W. CCRT included 5 cycles (optional 6th dose) of cisplatin 40 mg/m2 Q1W + EBRT then brachytherapy. Pts were stratified by planned EBRT type (intensity-modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] vs non-IMRT or non-VMAT), stage at screening (IB2-IIB vs III-IVA), and planned total radiotherapy dose (<70 Gy vs ≥70 Gy [EQ2D]). Primary endpoints are PFS per RECIST v1.1 by investigator and OS.Results
1060 pts were randomized to pembro + CCRT (n=529) or pbo + CCRT (n=531). At this analysis (January 8, 2024, data cutoff), median follow-up was 29.9 mo (range, 12.8-43.0). Pembro + CCRT showed a statistically significant improvement in OS compared with pbo + CCRT. The 36-mo OS rate was 82.6% with pembro + CCRT vs 74.8% with pbo + CCRT; median OS was NR in either group (HR=0.67 [95% CI, 0.50-0.90]; P=0.0040). The benefit of pembro + CCRT was generally consistent in all prespecified subgroups, including FIGO stages IB2-IIB (HR=0.89 [95% CI, 0.55-1.44]) and III-IVA (HR=0.57 [95% CI, 0.39-0.83]). Grade ≥3 TRAE incidence was 69.1% in the pembro + CCRT group and 61.3% in the pbo + CCRT group.
Conclusions
Pembro + CCRT showed a statistically significant and clinically meaningful improvement in OS vs pbo + CCRT in pts with high-risk LACC and had a manageable safety profile. These data provide further support for pembro + CCRT as a new standard of care for this population.
Clinical trial identification
NCT04221945; EudraCT: 2019-003152-37.
Editorial acknowledgement
Medical writing assistance was provided by Christine McCrary Sisk of Merck & Co., Inc., Rahway, NJ, USA. This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ,
Audio Journal of Oncology, October 6, 2025
An interview with:
James Larkin FRCP, PhD, Medical Oncologist, Professor, Royal Marsden Hospital, London
Checkpoint inhibitor therapy for advanced melanoma has achieved sustained responses and long-term overall survival, transforming the prognosis for as many as half of all patients. 10-year survival outcomes from the phase Ill CheckMate 067 trial of nivolumab plus ipilimumab in advanced melanoma were reported at the 2024 Annual Meeting of the European Society for Medical Oncology (ESMO) held in Barcelona.
Peter Goodwin, talked with study author, James Larkin FRCP PhD, Professor and Medical Oncologist at the Royal Marsden Hospital in London.
Audio Journal of Oncology: James Larkin FRCP PhD: IN: “There’s been breath-taking progress ………OUT: join me then, Good-bye!” 14:57secs
SOURCE:
Annals of Oncology:
https://www.annalsofoncology.org/article/S0923-7534(24)03864-X/fulltext
ESMO Abstract LBA43
- Larkin, Medicine Department, The Royal Marsden Hospital, London, UK
“10-y survival outcomes from the phase Ill CheckMate 067 trial of nivolumab plus ipilimumab in advanced melanoma”
Abstract LBA43
- Larkin, Medicine Department, The Royal Marsden Hospital, London, UK
“10-y survival outcomes from the phase Ill CheckMate 067 trial of nivolumab plus ipilimumab in advanced melanoma”
Background
In CheckMate 067, improved survival with nivolumab plus ipilimumab (NIVO + IPI) or NIVO alone v IPI has been demonstrated in patients (pts) with advanced melanoma. We now provide the final CheckMate 067 results (minimum f/u 10 y), the longest reported in a phase 3 study of an anti–programmed death (PD)-1–based therapy for any tumor type.
Methods
Pts with untreated advanced melanoma (N = 945) were randomly assigned 1:1:1 and stratified by PD-ligand (L)1 status, BRAF mutation status, and metastasis stage to receive NIVO (1 mg/kg) + IPI (3 mg/kg) Q3W for 4 doses, followed by NIVO (3 mg/kg) Q2W; NIVO (3 mg/kg) Q2W + placebo; or IPI (3 mg/kg) Q3W for 4 doses + placebo until progression or unacceptable toxicity. Co-primary endpoints were OS and PFS with NIVO + IPI or NIVO v IPI; melanoma-specific survival (MSS) was an exploratory endpoint.
Results
After a 10-y minimum f/u, median OS was 71.9 mo with NIVO + IPI, 36.9 mo with NIVO, and 19.9 mo with IPI. OS HRs were 0.53 (95% CI, 0.44–0.65) with NIVO + IPI vIPI and 0.63 (0.52–0.76) for NIVO v IPI, and benefit was consistent across subgroups (including PD-L1 expression and BRAF mutation status). Median MSS was not reached (NR) with NIVO + IPI (> 120 mo), 49.4 mo with NIVO, and 21.9 mo with IPI. In pts who had PFS for ≥ 3 y, 10-y MSS rates were 96% with NIVO + IPI, 97% with NIVO, and 88% with IPI. Only 8 pts, 4 in the NIVO + IPI arm and 4 in the NIVO arm, progressed beyond 60-mo of f/u. For pts in the NIVO + IPI arm who discontinued treatment during induction due to a treatment-related adverse event, 10-y OS rates were the same as the ITT group (43%) and MSS rates were similar (50% v 52%). Table: LBA43”
MORE:
James Larkin is a Medical Oncologist specialising in the treatment of cancers of the kidney and skin including melanoma.
Professor Larkin grew up in North Cornwall before taking a first in Natural Sciences from Cambridge University. He undertook clinical training in Oxford, qualifying in 1996. His general medical training was undertaken in London and in 2001 he won a Medical Research Council Research Fellowship for a Clinician, carrying out laboratory research leading to a PhD at the Institute of Cancer Research. His specialist training was completed at The Royal Marsden, where he was appointed as a Consultant in 2008.
His research is focussed on trying to understand cancer and its consequences better, as well as developing improved treatments, particularly with targeted therapies and immunotherapies. Globally, he is amongst the most highly cited researchers in both melanoma and kidney cancerThis link is external and opens in a new tab.
In 2018, he was elected as a Fellow of the Academy of Medical Sciences and in 2020 as an NIHR Senior Investigator. In 2022, he was appointed to roles as Head of The Royal Marsden Skin Unit, Royal Marsden Joint Training Programme Director for Medical Oncology and Lead of the Cancer Immunotherapy Theme at The Royal Marsden / Institute of Cancer Research NIHR Biomedical Research Centre.
Since 2024, he has hosted the educational podcast ‘Melanoma Matters’ with his US colleague Professor Sapna Patel, and in 2026 he will be Scientific Co-Chair of the Annual European Society of Medical Oncology meeting in Madrid.
Professor Larkin serves as a medical advisor to the patient advocacy group Melanoma UK, as a trustee of Action Kidney Cancer and sits on the Medical Advisory Board of the International Kidney Cancer Coalition.
An interview with: Jefferson DeKloe BSc, Department of Otolaryngology, Thomas Jefferson University, Philadelphia, PA
CHICAGO, USA—Although the take-up of vaccination for human papilloma virus (HPV) among girls and boys in the USA has been lower than in many other industrial countries, American researchers have now shown clearly that in addition to the prevention of cervical cancer in women, men have also been protected against HPV-related cancers.
At the 2024 American Society of Clinical Oncology Annual (ASCO) Meeting in Chicago a new study of HPV vaccination of girls and boys in the United States revealed a real-world reduction of oral, plus head and neck cancers in men, as well confirming the prevention of cervical cancers in women, even though uptake of the vaccine in the US had been sub-optimal. The study looked at HPV-associated cancer incidence in a retrospective cohort analysis of patients from the TriNetX Collaborative Network.
At the ASACO meeting Peter Goodwin met up with the lead author of the research, Jefferson DeKloe BSc, from the Department of Otolaryngology at Thomas Jefferson University in Philadelphia USA.
Audio Journal of Oncology, with: Jefferson DeKloe BSc
IN: “HPV Vaccination …..OUT: ……, I’m Peter Goodwin”. 6:00secs
https://meetings.asco.org/abstracts-presentations/231759
“Effects of HPV vaccination on the development of HPV-related cancers: A retrospective analysis of a United States-based cohort.”
https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.10507
Effects of HPV vaccination on the development of HPV-related cancers: A retrospective analysis of a United States-based cohort.
ALSO:
https://www.sciencedirect.com/science/article/pii/S1043661825002762
HPV vaccination and malignancy risks beyond cervical cancer: A retrospective global cohort study
Authors: Christian Seebauer, Mohamed Faluogy, Peter Sieg , Henning Olbrich, Ralf Ludwig
Department of Oral and Maxillofacial Surgery/Plastic surgery, University Medicine Lübeck, Ratzeburger Allee 160, Lübeck 23538, Germany
Department of Dermatology, Allergy, and Venerology, University of Lübeck, Ratzeburger Allee 160, Lübeck 23538, Germany
Department of Dermatology, Allergy, and Venerology, Institute of Experimental Dermatology, University of Lübeck, Comprehensive Center for Inflammation Medicine, University-Hospital Schleswig-Holstein, Ratzeburger Allee 160, Lübeck 23538, Germany
Received 28 April 2025, Revised 5 July 2025, Accepted 6 July 2025, Available online 11 July 2025, Version of Record 14 July 2025.
HPV vaccination significantly reduced hypopharyngeal and laryngeal cancer risk.
Vaccination was associated with a marked decrease in leukemia incidence.
No significant protection observed for rectal, anal, or oral cavity cancers.
HPV vaccination halved all-cause mortality at 8- and 20-year follow-up.
Data support possible HPV involvement in hematopoietic and neuronal tissues.
Abstract:
While HPV vaccination is well established for the prevention of cervical cancer, its broader oncological effects remain insufficiently characterized. Emerging evidence suggests potential protective effects against non-cervical malignancies; however, comprehensive long-term data are limited. We conducted a global, retrospective cohort study utilizing electronic health records from the TriNetX network. Individuals vaccinated against HPV at age 8 years or older were propensity score-matched to unvaccinated controls. Outcomes included the incidence of malignancies in the head-and-neck, gastrointestinal, anogenital, neuronal, and hematologic systems, as well as all-cause mortality, assessed over 8- and 20-year follow-up periods. Kaplan–Meier survival analysis and hazard ratios (HRs) were employed. HPV vaccination was associated with significant reductions in the risk of hypopharyngeal and laryngeal carcinomas (8-year HR: 0.19; 95 % CI: 0.057–0.631; p = 0.0025; 20-year HR: 0.227; 95 % CI: 0.067–0.764; p = 0.0092) and leukemia (8-year HR: 0.461; p = 0.0035; 20-year HR: 0.443; p = 0.0019). No significant protection was observed for rectal, anal, oral cavity, or prostate cancers. All-cause mortality was reduced by nearly half among vaccinated individuals (8-year HR: 0.543; 20-year HR: 0.536; both p < 0.0001). Beyond epithelial malignancies, HPV vaccination may confer systemic cancer protection, particularly in hematologic and potentially neuronal tissues. These findings suggest a broader biological impact of HPV vaccination than previously recognized and underscore the need for mechanistic studies investigating HPV’s oncogenic pathways. If validated, these results could prompt the expansion of vaccination strategies to encompass broader indications and wider population coverage.
An interview with Rebecca Dent MD, Deputy Chief Executive Officer, National Cancer Centre, Singapore, ESMO 2024 Scientific Chair.
ESMO Previous Highlights: Neo-Adjuvant Therapy for Triple Negative Breast Cancer, Checkpoint Inhibition, AI, Cancer Vaccines, and More ……”
BARCELONA, Spain—At the last Annual Meeting of the European Society for Medical Oncology (ESMO), medical oncologist Rebecca Dent MD, Deputy Chief Executive Officer at the National Cancer Centre in Singapore, told Peter Goodwin what had, for her, been the key areas of progress in cancer medicine announced at the meeting in which significant advances had been made.
Audio Journal of Oncology with Rebecca Dent MD IN: [Goodwin] “With the 2025 meeting of ESMO about to happen …. OUT: ….in Singapore. Thanks very much. 13:13 secs
https://www.esmo.org/meeting-calendar/esmo-congress-2024/programme
MORE:
Professor Rebecca Dent MD MSc is a career-long clinical and translational researcher as well as education-focused, academic clinician with sub-specialist interest in all aspects of triple negative breast cancer (TNBC) and young women with breast cancer.
Prof. Dent achieved her MD from McMaster University in Hamilton, Ontario, Canada and then completed her internal medicine and medical oncology residency at the Princess Margaret Hospital and the Sunnybrook Odette Cancer Center in Toronto, Canada. This was followed by a fellowship in breast cancer, supported by a Marion Walker Women’s Health Scholarship, and MSc in Clinical Epidemiology and Statistics at the University of Toronto. During her training Prof Dent was fortunate to have completed electives across Canada, the US (Memorial Sloan Kettering), France (Institut Marie Curie) and the Philippines (Philippine General Hospital).
In her North American academic career, Prof Dent served as Chair of the locally advanced breast cancer program and Head, Breast Cancer Clinical Trials Unit at the Sunnybrook Odette Cancer Center from 2008-2011. Her seminal publication whilst in Toronto was a Clinical Cancer Research publication, one of the first to describe what is now known as triple negative with almost 5,500 citations for this individual paper (Dent R et al. Clin Ca Res 2007). She was the PI of one of the first Phase I PARP inhibitor trials in unselected TNBC in combination with taxane chemotherapy and she served as a reviewer for the National Cancer Institute of Canada (NCIC) grants committee. As a consultant at the Sunnybrook Odette Cancer Center, she supervised a number of residents and fellows and was awarded an Outstanding Teaching Award by the University of Toronto.
Prof Dent has participated in the ASCO Leadership Development Program and served on a number of ASCO Committees: Education including Chair, Breast Track and Member of the Breast Scientific Committee (ER/HER2 track), as well as on the Editorial Board of the Journal of Clinical Oncology (JCO).
In February 2011, Prof Dent moved to Singapore where she is now senior consultant at the National Cancer Center in Singapore (NCCS). Recognizing the need for pan-Asian regional educational interaction Prof Dent co-founded and co-chaired nine Asia Pacific Breast Cancer Summits (https://apbcs.org). Consequently Prof Dent was involved in the establishment of the ESMO Asia meeting subsequently serving as Scientific Chair and Co-Chair Breast Track. Prof Dent has co-chaired the ESMO Breast Preceptorship in Singapore since 2017 and sits on the pan-Asian ESMO adapted guidelines committee as well as the Advanced Breast Cancer ESMO guideline committee. Prof Dent serves as a scientific committee member of the ASCO Breakthrough Asia Meeting. Prof Dent is currently Chair of the ESMO Nomination Committee and a member of the ESMO Council.
Prof Rebecca Dent has over 18,000 citations and an h-index over 50. She sits on the Editorial Board of The Lancet Oncology. She has been invited as an oral and plenary discussant at ESMO as well as an invited speaker at numerous meetings for ASCO, ESMO Asia, and other meetings across Asia such as the Japanese Society of Medical Oncology and Korean Society of Medical Oncology. Prof Dent is a steering committee member and PI for a number of large international trials evaluating novel agents in the treatment of TNBC. Funding was secured for a novel investigator initiated global study evaluating the role of PARP inhibition with or without immune checkpoint inhibition in platinum sensitive TNBC which has just completed recruitment in the US, Korea and in Singapore (The DORA study). This is a pivotal Duke NUS Singapore and Duke USA collaboration.
As of October 2018, Prof Dent has been Head of the department of Medical Oncology at the National Cancer Center Singapore (NCCS) at SingHealth. NCCS has recently been designated as a comprehensive cancer center and Prof Dent was appointed Chairman of the Division of Medical Oncology in 2021.
Prof Dent maintains a busy clinical practice, as well as teaching medical students at Duke-NUS. This has been recognized with a star award for Quality National Service and the SingHealth Outstanding Clinician Award. Most recently in 2023 she was one of the Singapore National Health Quality Service Superstar award winners.
Audio Journal of Oncology interview with:
Bart Neyns MD PhD, Vrije Universiteit Brussel, Faculty of Medicine and Pharmacy, Medical Oncology Department, Brussels, Belgium
BARCELONA, Spain—Intracranial administration of autologous dendritic cells was combined with combination checkpoint inhibition in a phase 1 study of patients with recurrent glioblastoma that reported marked clinical responses to the European Society for Medical Oncology (ESMO) annual meeting in Barcelona.
Cells harvested from each patient were injected directly into the brain tissue resection cavity lining after surgery. Patients also received intra-cranial injections of the checkpoint inhibitor combination: nivolumab plus ipilimumab.
At the conference, Peter Goodwin discussed the research with lead author of the study, Bart Neyns MD PhD, Head of Medical Oncology at the Vrije Universiteit, Brussel, in the University Hospital Brussels Faculty of Medicine & Pharmacy, Brussels, Belgium.
Audio Journal of Oncology interview with: Bart Neyns MD PhD, Vrije Universiteit Brussel, Faculty of Medicine and Pharmacy, Medical Oncology Department, Brussels, Belgium
IN : “Patients with recurrent glioblastoma …. OUT:…from me, Peter Goodwin, goodbye 10:54 secs
SOURCE: ESMO 2024 Barcelona
ESMO Abstract 441O
- Neyns , Medical Oncology Department, Vrije Universiteit Brussel – Faculty of Medicine & Pharmacy, Brussels, Belgium
“A phase I clinical trial on the intracranial administration of autologous CD1c(BDCA-1)+/CD141(BDCA-3)+ myeloid dendritic cells (myDC) in combination with ipilimumab (IPI) and nivolumab (NIVO) in patients with recurrent high-grade glioma (rHGG)”
Reference:
CNS tumours Volume 35, Supplement 2S406-S407 September 2024Authors:
-
Neyns1 ∙ I. Dirven1 ∙ L. Lescrauwaet2 ∙ M. Cammaert1 ∙ W. Geens2 ∙ X. Geeraerts1 ∙ L. Stevens1 ∙ S. Brock3 ∙ M. Kockx4 ∙ H. Everaert5 ∙ A-M. Van Binst6 ∙ S. Tuyaerts1 ∙ J. Duerinck7
-
Medical Oncology Department, Vrije Universiteit Brussel – Faculty of Medicine & Pharmacy, Brussels, Belgium
-
Neurosurgery, UZ Brussel – Universitair Ziekenhuis Brussel, Jette, Belgium
-
Pathology, UZ Brussel – Universitair Ziekenhuis Brussel, Jette, Belgium
-
Pathology Department, CellCarta, Antwerpen, Belgium
-
Nuclear Medicine, Vrije Universiteit Brussel – Faculty of Medicine & Pharmacy, Brussels, Belgium
-
Radiology Department, Vrije Universiteit Brussel – Faculty of Medicine & Pharmacy, Brussels, Belgium
-
Neurosurgery Department, Vrije Universiteit Brussel – Faculty of Medicine & Pharmacy, Brussels, Belgium
https://www.audiomedica.com/wp-content/2025/09/241011-Bart-Neyns-ESMO-AJO-PRODUCTION-MASTER.mp3Background
Intracranial admin of NIVO and IPI following the resection of rHGG is safe and has resulted in encouraging survival (J Duerinck et al. JITC 2021). myDC play a pivotal role in initiating an adaptive anti-tumor immune response and licensing of immune anti-tumor effector cells within the tumor microenvironment.
Methods
rHGG pts (after prior RT and TMZ, <8 mg methylprednisolone QD), underwent a leukapheresis followed by isolation/cryopreservation of myDC. NIVO (10 mg IV) was administered preoperatively. myDC (5-, 10-, or 20.106 cells) were injected into the brain tissue lining the resection cavity (iCer) following a maximal safe resection (MSR) or intratumorally (iTum) following a stereotactic biopsy (STX). IPI (5 mg) plus NIVO (10 mg) were co-injected iCer or iTum with the myDC. Postoperative NIVO was administered intracavitary (iCav, 10 mg) and intravenously (IV, 10 mg) Q2w (max 11x).
Results
21 pts (13 M; med 49 y [range 20 -78]; IDHwt 17 pts, ECOG PS 0 or 1: 18-, 3 pts) underwent procurement of myDC; intraoperative administration of myDC was preceded by MSR in 19 pts, and STx in 2 pts. Respectively 6, 3, and 12 pts were treated at the 3 myDC dose levels. All pts received the peri-op iTum/iCer/IV-admin of IPI and NIVO as planned. The median postop iCav and IV NIVO-admin was 7 (range 0-11) and 8 (0-11). Study treatment was discontinued early for PD in 9- and AE in 3 pts. Most important TRAEs: bacterial colonization of the Ommaya reservoir (n=4), craniotomy wound dehiscence (n=2), and bacterial meningitis (n=1). At DBL (01MAY2024), 6 pts (29%) remain progression-free (incl. 3 pts with >2y PFS). PFS (med. 24w [95% CI 8- 39]) is superior when compared to the pts (n=70) with resectable rHGG treated in 4 other cohorts of the GlITIpNi trial (p=0.003). When including the durable benefit from bevacizumab at first PD in 3 pts, PFS compared favorably to a historical pooled cohort (n=469) of rHGG treated with VEGF(R)-inhibitors (p=0.007). The 1-year OS-rate was 50% [95% CI 24-76].
Conclusions
Intracranial administration of myDC combined with IPI/NIVO is feasible, safe and associated with encouraging survival, deserving further investigation.
An interview with:
Victor Velculescu MD PhD, Co-director, Cancer Genetics & Epigenetics Program, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
SAN DIEGO, USA—A blood test using an artificial intelligence DNA pattern recognition system that brings earlier, more certain detection of ovarian cancer was reported at the American Association for Cancer Research Annual Meeting held in San Diego.
The test analyses patterns of fragments of circulating DNA (called DNA fragmentomes). When combined with analysis of circulating tumor protein markers these were found to be highly correlated with ovarian cancer. The test uses the DELFI (DNA Evaluation of Fragments for early Interception) system that has already been established for early detection of lung cancer.
At the San Diego conference lead author of the research, Victor Velculescu MD PhD, Co-director, Cancer Genetics & Epigenetics Program, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland discussed the findings with Peter Goodwin.
AUDIO JOURNAL OF ONCOLOGY with: Victor Velculescu MD PhD. IN: “Hello, Peter Goodwin here …..OUT: ……..for the Audio Journal of Oncology, I’m Peter Goodwin” 13:49secs
2024 AACR ABSTRACT:
Abstract 773: Early detection of ovarian cancer using cell-free DNA fragmentomes
AUTHORS:
Akshaya V. Annapragada; Jamie E. Medina; Victor E. Velculescu et al.
https://aacrjournals.org/cancerres/article/83/7_Supplement/773/719566/Abstract-773-Early-detection-of-ovarian-cancer
https://pubmed.ncbi.nlm.nih.gov/39345137/
Early Detection of Ovarian Cancer Using Cell-Free DNA Fragmentomes and Protein Biomarkers
Jamie E Medina # 1, Akshaya V Annapragada # 1, Pien Lof 2, Sarah Short 1, Adrianna L Bartolomucci 1, Dimitrios Mathios 1, Shashikant Koul 1, Noushin Niknafs 1, Michaël Noë 1, Zachariah H Foda 1, Daniel C Bruhm 1, Carolyn Hruban 1, Nicholas A Vulpescu 1, Euihye Jung 3, Renu Dua 1, Jenna V Canzoniero 1, Stephen Cristiano 1, Vilmos Adleff 1, Heather Symecko 4, Daan van den Broek 5, Lori J Sokoll 1, Stephen B Baylin 1, Michael F Press 6, Dennis J Slamon 7, Gottfried E Konecny 7, Christina Therkildsen 8, Beatriz Carvalho 9, Gerrit A Meijer 9, Claus Lindbjerg Andersen 10 11, Susan M Domchek 3 4, Ronny Drapkin 3 4, Robert B Scharpf 1, Jillian Phallen 1, Christine A R Lok 2, Victor E Velculescu 1
Affiliations* 1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. * 2Department of Gynecologic Oncology, Centre of Gynecologic Oncology Amsterdam, Antoni van Leeuwenhoek Hospital-The Netherlands Cancer Institute, Amsterdam, the Netherlands. * 3Penn Ovarian Cancer Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. * 4Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. * 5Department of Laboratory Medicine, Antoni van Leeuwenhoek Hospital-The Netherlands Cancer Institute, Amsterdam, the Netherlands. * 6Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California. * 7David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. * 8Department of Surgical Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark. * 9Department of Pathology, Antoni van Leeuwenhoek Hospital-The Netherlands Cancer Institute, Amsterdam, the Netherlands. * 10Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark. * 11Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Ovarian cancer is a leading cause of death for women worldwide, in part due to ineffective screening methods. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker [cancer antigen 125 (CA-125) and human epididymis protein 4 (HE4)] analyses to evaluate 591 women with ovarian cancer, with benign adnexal masses, or without ovarian lesions. Using a machine learning model with the combined features, we detected ovarian cancer with specificity >99% and sensitivities of 72%, 69%, 87%, and 100% for stages I to IV, respectively. At the same specificity, CA-125 alone detected 34%, 62%, 63%, and 100%, and HE4 alone detected 28%, 27%, 67%, and 100% of ovarian cancers for stages I to IV, respectively. Our approach differentiated benign masses from ovarian cancers with high accuracy (AUC = 0.88, 95% confidence interval, 0.83–0.92). These results were validated in an independent population. These findings show that integrated cfDNA fragmentome and protein analyses detect ovarian cancers with high performance, enabling a new accessible approach for noninvasive ovarian cancer screening and diagnostic evaluation.
Significance:
There is an unmet need for effective ovarian cancer screening and diagnostic approaches that enable earlier-stage cancer detection and increased overall survival. We have developed a high-performing accessible approach that evaluates cfDNA fragmentomes and protein biomarkers to detect ovarian cancer.
Introduction
Ovarian cancer is a leading cause of death in women worldwide, with more than 300,000 new cases and nearly 200,000 deaths globally each year (1). In the United States during 2024, approximately 19,600 new cases will be diagnosed and 12,700 women will die from ovarian cancer (2). The most common form of ovarian cancer is epithelial ovarian cancer, which comprises four major subtypes: serous, clear cell, mucinous, and endometrioid carcinomas. According to the Surveillance, Epidemiology, and End Results database, for individuals with detected invasive epithelial ovarian cancer, the estimated 5-year survival is 93% and 75% for localized (stage I) or regional (stage II or stage IIIA1 with regional lymph node involvement) disease, respectively, compared with 31% for distant disease (remaining stage III or stage IV; refs. 3, 4). Unfortunately, ovarian cancer is usually detected in advanced stages (stages III and IV) due to nonspecific clinical symptoms at earlier stages and the lack of an effective screening approach (3). Consequently, there is a clear unmet clinical need for the development of highly specific and sensitive assays to detect ovarian cancer in its earliest stages.
Ovarian cancer screening trials such as the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (5), the U.K. Collaborative Trial of Ovarian Cancer Screening (UKCTOCS; ref. 6), and the Normal Risk Ovarian Screening Study (ref. 7) have shown that existing biomarkers, including cancer antigen 125 (CA-125), may provide a shift toward detection of earlier stages of cancer but not a survival benefit, likely because of suboptimal detection of ovarian cancers. These analyses open the door to new and more effective approaches aimed at identifying combinations of biomarkers with improved performance for early ovarian cancer detection. Such approaches would need to be affordable, accessible, and have high performance for high-grade serous ovarian carcinoma (HGSOC), which is more aggressive, typically detected in late stages, and responsible for the majority of ovarian cancer deaths (8).
A secondary clinical need also exists in determining whether women presenting with ovarian masses have benign or malignant lesions. In this setting, preoperative malignancy classification is challenging and may lead to unnecessary procedures. A number of biomarkers have been proposed in this setting, including CA-125 and human epididymis protein 4 (HE4; refs. 9–11). Prediction models using a combination of multiple protein biomarkers as well as age and menopausal status (12), the risk of malignancy index (ref. 13), and other ultrasound classifications (International Ovarian Tumor Analysis; ref. 14) have been developed, but these vary in accuracy, performance, and ease of use in a clinical setting.
Analyses of circulating cell-free DNA (cfDNA) provide another approach for early cancer detection in the screening or diagnostic settings. Approaches for ovarian cancer have included identification of tumor-specific mutations (15, 16), or alterations in DNA methylation (17), or specific repeat sequences (18, 19); however, these approaches have had limited sensitivities for early-stage disease, may be confounded by alterations in white blood cells (20), and have not been validated for clinical use. An emerging approach of cfDNA analyses have focused on the “cfDNA fragmentome,” defined as the genome-wide compendium of cfDNA fragments in the circulation, providing an integrated view of the chromatin, genome, epigenome, and transcriptome states of normal and cancer cells of an individual. Recent cfDNA fragmentome analyses using low-coverage whole-genome sequencing (WGS) combined with machine learning using DNA evaluation of fragments for early interception (DELFI) have demonstrated high sensitivity for early detection across lung (21), liver (22), and other cancer types (23–26) using an accessible, cost-efficient approach (27) that is not confounded by clonal hematopoiesis (20, 28).
In this study, we present a method to detect ovarian cancer using cfDNA fragmentomes combined with protein biomarkers. This multianalyte combination has the benefit of utilizing genome-wide multifeature fragmentation analyses together with complementary protein biomarkers CA-125 and HE4 from the same blood draw that may have utility in both the screening and diagnostic settings.
Results
Clinical Cohorts
Blood samples in the discovery cohort were collected from women with ovarian cancer (n = 94), with benign adnexal masses (n = 203), or without any known ovarian lesions (n = 182), who were part of previously reported prospective diagnostic or screening efforts at hospitals in the Netherlands and Denmark (Table 1; Supplementary Table S1; refs. 9, 21, 23, 29). For the validation cohort, we analyzed samples from patients prospectively collected at the University of Pennsylvania or through a commercial source in the United States (n = 40 patients with ovarian cancer, n = 50 patients with benign ovarian masses, and n = 22 without known ovarian lesions; Table 1; Supplementary Table S1). The patients analyzed were largely representative of ovarian cancer subtypes, including high-grade serous (HGSOC), low-grade serous (LGSOC), clear cell, mucinous, and endometrioid ovarian cancers, across all International Federation of Gynecology and Obstetrics (FIGO) stages (Table 1).
NEWS RELEASE:
Artificial Intelligence Analysis of DNA Fragmentomes and Protein Biomarkers Noninvasively Detects Ovarian Cancer
April 9, 2024
SAN DIEGO – A blood-based machine learning assay that combines cell-free DNA (cfDNA) fragment patterns and levels of the proteins CA125 and HE4 could differentiate patients with ovarian cancer from healthy controls or patients with benign ovarian masses, according to a retrospective study presented at the American Association for Cancer Research (AACR) Annual Meeting 2024, held April 5-10.
Federal statistics list ovarian cancer as the fifth most common cause of cancer deaths among women in the United States, with a five-year survival rate of approximately 50%. Part of what makes ovarian cancer so deadly is that it does not typically cause symptoms in the early stages of disease, explained Jamie Medina, PhD, a postdoctoral fellow at the Johns Hopkins Kimmel Cancer Center.
“The lack of efficient screening tools, combined with the asymptomatic development of ovarian cancer, contributes to late diagnoses when effective treatment options are limited,” said Medina, who presented the study alongside co-first author Akshaya Annapragada, an MD/PhD student at the Johns Hopkins University School of Medicine. “A cost-effective, accessible detection approach could change clinical paradigms of ovarian cancer screening and potentially save lives.”
Liquid biopsy technologies, in which researchers analyze patients’ blood for evidence of tumor-derived DNA, have been explored as a way to noninvasively detect a variety of cancers; however, they have not always been useful in ovarian cancer, Medina explained. DELFI (DNA Evaluation of Fragments for early Interception), utilizes a newer method of liquid biopsy analysis, called fragmentomics, that has shown promise in improving the accuracy of such tests. The approach is based on detecting in the circulation changes in the size and distribution of cfDNA fragments across the genome, or the fragmentome.
“Because cancer cells are rapidly growing and dying and have chaotic genomes as compared to healthy cells, patients with cancer have different patterns of DNA fragments in their blood than patients without cancer,” Medina said. “By carefully analyzing these fragments across the entire human genome, we can detect subtle patterns indicating the presence of cancer.”
Medina, Annapragada, and colleagues analyzed fragmentomes from individuals with and without ovarian cancer using DELFI. They trained a machine learning algorithm to integrate the fragmentome data with plasma levels of two known biomarkers of ovarian cancer: the proteins CA125 and HE4.
“Ovarian cancer is an incredibly deadly disease with no great biomarkers for screening and early intervention,” said Victor Velculescu, MD, PhD, FAACR, senior author of the study, a professor of oncology, and codirector of the Cancer Genetics and Epigenetics Program at the Johns Hopkins Kimmel Cancer Center. “Our goal was to overcome this challenge by combining genome-wide cell-free DNA fragmentation with protein biomarkers to develop a new high-performance approach for early detection of ovarian cancer.”
The researchers analyzed plasma from 134 women with ovarian cancer, 204 women without cancer, and 203 women with benign adnexal masses. They used the data to develop two models: one to examine
ovarian cancer screening in an asymptomatic population and the other to noninvasively differentiate benign masses from cancerous ones.
At a specificity of over 99% (nearly no false positives), the screening model identified 69%, 76%, 85%, and 100% of ovarian cancer cases staged I-IV, respectively; the area under the curve (a measure of accuracy that increases as the value approaches 1) was 0.97 across all stages, much higher than the performance of current biomarkers. For comparison, an analysis of CA125 levels alone identified 40%, 66%, 62%, and 100% of cases staged I-IV, respectively.
The diagnostic model was able to differentiate ovarian cancer from benign masses with an area under the curve of 0.87.
The group intends to validate their models in larger cohorts to strengthen the associations observed here, Velculescu said, but he found the current data encouraging. “This study contributes to a large body of work from our group demonstrating the power of genome-wide cell-free DNA fragmentation and machine learning to detect cancers with high performance,” he said. “Our findings indicate that this combined approach resulted in improved performance for screening compared to existing biomarkers.”
Limitations of this study include a relatively small sample size, a study population primarily comprised of American and European patients, and the retrospective nature of the analysis.
Funding for this study was provided by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Stand Up To Cancer, the Gray Foundation, The Honorable Tina Brozman Foundation, the Commonwealth Foundation, The Mark Foundation for Cancer Research, the COLE Foundation, Delfi Diagnostics, and the U.S. National Institutes of Health. Medina, Annapragada, and Velculescu are inventors on patent applications related to the use of cfDNA for cancer detection that have been submitted by Johns Hopkins University and licensed to Delfi Diagnostics. Velculescu is also an inventor on patent applications that have been submitted by Johns Hopkins University and licensed to Labcorp, Qiagen, Sysmex, Agios, Genzyme, Esoterix, Ventana, and ManaT Bio. Velculescu is a founder and member of the Board of Directors of Delfi Diagnostics, a company for which he owns stock and Johns Hopkins University owns equity. Velculescu is also an advisor to Virion Therapeutics and Epitope.
Audio Journal of Oncology: Sept 23rd, 2025
An interview with:
Timothy Yap MD PhD MBBS, Professor of Investigational Cancer Therapeutics, Head of Clinical Development, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, USA
SAN DIEGO, USA—Breast, ovarian, pancreatic, prostate and other solid tumors with mutations sensitizing them to poly ADP ribose polymerase (PARP) inhibition, could potentially be controlled better and with less toxicity with the new selective PARP-1 inhibitor saruparib than with existing licensed agents which inhibit both PARP 1 and PARP 2. That’s according to early results from the PETRA study reported to the San Diego meeting of the American Association for Cancer Research (AACR).
Timothy Yap MD PhD MBBS, Professor of Investigational Cancer Therapeutics and Head of Clinical Development in the Therapeutics Discovery Division of the University of Texas MD Anderson Cancer Center in Houston, reported early clinical data from the PETRA study. After his talk at the AACR conference he discussed the findings with Peter Goodwin.
Timothy Yap MD PhD MBBS: AUDIO JOURNAL OF ONCOLOGY: IN (SARAH M AXWELL): A new class of PARP inhibitor … ….OUT: from me, Sarah Maxwell, Good-bye. 18:45 secs
WHAT IS SARUPARIB? : “Saruparib is an investigational new drug that is being evaluated for the treatment of cancer. It is a first-in-class selective inhibitor of poly-ADP ribose polymerase 1, designed to treat cancers with homologous recombination repair deficiencies as a result of mutations in BRCA1, BRCA2, PALB2, RAD51C, or RAD51D genes.”
AACR ABSTRACT:
Next-generation PARP Inhibitor Demonstrates Clinical Benefit in Patients with
Homologous Recombination Repair-deficient Breast Cancer
PETRA: first-in-human Phase 1/2a trial of the first-in-class new generation poly-ADP-ribose polymerase-1 selective inhibitor (PARP1i) saruparib (AZD5305) in patients (pts) with advanced solid tumors with BRCA1/2, PALB2 or RAD51C/D mutations
https://aacrjournals.org/cancerres/article/82/12_Supplement/CT007/701955/Abstract-CT007-PETRA-First-in-class-first-in-human
AACR Abstract CT007:
PETRA: First in class, first in human trial of the next generation PARP1-selective inhibitor AZD5305 in patients (pts) with BRCA1/2, PALB2 or RAD51C/D mutations
Abstract
Background: AZD5305 is a potent, highly selective PARP1 inhibitor and trapper with superior preclinical tolerability, target engagement and efficacy vs 1st generation dual PARP1/2 inhibitors (PARPi). This is the first report of the ongoing Phase 1/2a PETRA (NCT04644068) trial.
Citation Format: Timothy A. Yap, Seock-Ah Im, Alison M. Schram, Adam Sharp, Judith Balmana, Richard D. Baird, Jessica S. Brown, Maria Schwaederle, Elizabeth A. Pilling, Ganesh Moorthy, Spiros Linardopoulos, Adam Dowson, Carol Pound, Edit Lukacs, Sabina Cosulich, Stephen J. Luen. PETRA: First in class, first in human trial of the next generation PARP1-selective inhibitor AZD5305 in patients (pts) with BRCA1/2, PALB2 or RAD51C/D mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT007.
Methods: Pts with advanced breast, ovarian, prostate or pancreatic cancer bearing germline or somatic BRCA1/2, PALB2 or RAD51C/D mutations received AZD5305 QD PO until disease progression. ECOG PS 0-2 and Hb ≥9.0 g/dL were required. Prior PARPi and platinum therapy were permitted. The primary objective was safety; secondary objectives included pharmacokinetics (PK) and pharmacodynamics in tumor and/or blood samples and response by RECIST v1.1, CA125 or PSA. Exploratory genomic analyses included zygosity evaluation and ctDNA response monitoring.
Results: At data cutoff (Nov 17, 2021), 46 pts received AZD5305 10-90 mg QD (43.5% had prior PARPi; median 3.5 prior lines of therapy). AZD5305 was well tolerated across all doses without DLTs. PK exposures were dose-proportional. Steady-state Ctrough was higher than 1st generation PARPi: specificaly 6.3 and 31.9 fold above target effective concentration at 10 and 90 mg, respectively. PARylation inhibition was ≥90% at 10-40 mg QD (PBMCs) confirming target engagement. 7/25 (28%) pts had objective responses: 5 RECIST PRs (3 confirmed) and 2 additional pts with PSA50 responses (1 confirmed), including platinum- and PARPi-resistant pts. 13/22 (59%) RECIST-measurable pts had SD or PR up to 51+ weeks. ctDNA declined on treatment in 7/13 (54%) evaluable pts (3 complete, 4 >50% reductions) across doses.
Conclusions: AZD5305 is a highly selective PARP1 inhibitor and trapper with excellent physiochemical properties and a wide therapeutic index. It led to maximal target engagement and showed promising clinical activity with favorable tolerability at exposures surpassing those of 1st generation PARPi.
MORE: (AACR RELEASE):
Next-generation PARP Inhibitor Demonstrates Clinical Benefit in Patients with Homologous Recombination Repair-deficient Breast Cancer
Drug has higher selectivity for PARP1, improving safety and tolerability
SAN DIEGO – Saruparib, a selective inhibitor of poly-ADP ribose polymerase 1 (PARP1), demonstrated a promising objective response rate and progression-free survival in patients with certain homologous recombination repair (HRR)-deficient breast cancers, according to results from the phase I/II PETRA trial, presented at the American Association for Cancer Researc 2024 Annual Meeting in San Diego.
Although blocking the enzyme PARP1 may be sufficient to prevent DNA repair in HRR-deficient tumors, all PARP inhibitors currently approved by the U.S. Food and Drug Administration (FDA) block both PARP1 and PARP2, which can limit utility because of toxicity, explained Timothy A. Yap, MBBS, PhD, professor of Investigational Cancer Therapeutics and vice president and head of clinical development in the Therapeutics Discovery Division at The University of Texas MD Anderson Cancer Center, who presented the study.
“When we were developing first-generation PARP inhibitors, we weren’t able to increase the doses above a certain threshold because of toxicity,” Yap said. “By designing selective PARP1 inhibitors, we have a great opportunity to improve safety, tolerability, pharmacokinetics, pharmacodynamics, efficacy, and combinability with other therapies.”
Saruparib, a PARP1-specific inhibitor, showed promising tumor growth inhibition in preclinical models of breast ovarian pancreatic and prostate cancer harboring HRR deficiency mutations. Because saruparib was less toxic than other PARP inhibitors, it could be given at higher doses.
“The properties of saruparib enable patients to reach high drug pharmacokinetic exposure levels and pharmacodynamic target engagement,” Yap said. “This means that patients may be able to stay on the optimal dose for a longer duration due to fewer dose interruptions and reductions, which may ultimately improve efficacy.”
PETRA is a multicenter phase I/II clinical trial evaluating the safety, tolerability, and efficacy of saruparib in 306 patients with previously treated (including ≤1 prior PARP inhibitor in the dose escalation phase and PARP inhibitor-naive breast cancer patients in the dose expansion phase) HRR-deficient breast, ovarian, pancreatic, or prostate cancer. Patients had tumors with mutations in one of five HRR genes: BRCA1, BRCA2, PALB2, RAD51C, or RAD51D.
Patients were treated at doses ranging from 10 to 140 mg saruparib daily; 60 mg daily was chosen as the recommended dose for further clinical development. Among the 31 breast cancer patients treated with 60 mg saruparib, the objective response rate was 48.4%, the median duration of response was 7.3 months, and the median progression-free survival was 9.1 months.
In the cohort of 141 patients who received the 60 mg dose across all cancer types, adverse events were observed in 92.2% of patients and 12.1% of patients experienced a serious adverse event. Adverse events related to saruparib were observed in 76.6% of patients, and 2.1% of patients had a serious adverse event related to the drug; 3.5% of patients discontinued treatment due to adverse events related to saruparib.
Yap noted that the adverse events profile from this phase I/II trial of heavily pretreated patients compared favorably to those from phase III trials testing other PARP inhibitors in treatment-naïve patients. “The low rate of dose reductions observed with saruparib suggests a very manageable safety profile that we believe will enable patients to stay longer at the optimal dose and therefore maximize the opportunity for long-term benefit,” Yap said.
Pharmacokinetic analyses showed that, at all dose levels, patients maintained higher blood concentrations of saruparib than typically observed with other PARP inhibitors. At the molecular level, saruparib inhibited around 90% of PARP activity in tumor tissue collected from biopsies.
“The excellent safety and tolerability profile, along with the favorable pharmacokinetic and pharmacodynamic properties, may enable patients to remain on saruparib treatment with sustained maximal target engagement and limited dose reductions or discontinuation,” Yap said.
Limitations of this study include its single-arm design and small sample size.
This study was funded by AstraZeneca. Yap is head of clinical development in the Therapeutics Discovery Division at The University of Texas MD Anderson Cancer Center, which has licensed therapeutics to Artios Pharma. He serves or has served as a consultant for 858 Therapeutics, Inc., AbbVie, Acrivon Therapeutics, Adagene, Aduro Biotech, Inc., Almac, Amgen, Amphista Therapeutics, Artios Pharma, Astex Pharmaceuticals, AstraZeneca, Athena Therapeutics, Atrin Pharmaceuticals, Avenzo Therapeutics, Avoro Capital Advisors, Axiom Real-Time Metrics, Baptist Health System, Bayer, BeiGene, BioCity Biopharma, Blueprint Medicines, Boxer Capital, BridGene Biosciences, Bristol Myers Squibb, C4 Therapeutics, Inc., Calithera Biosciences, Cancer Research UK, Carrick Therapeutics, Circle Pharma, Inc., Clovis Oncology, Cybrexa Therapeutics, Daiichi Sankyo, Dark Blue Therapeutics Ltd., Debiopharm, Diffusion Pharmaceuticals, Duke Street Bio Ltd., EcoR1 Capital Fund, Ellipses Pharma, EMD Serono, Inc., Entos Pharmaceuticals, FoRx Therapeutics AG, F-star Therapeutics, Genesis Therapeutics, Genmab, Glenmark Pharmaceuticals, GLG Pharma, Globe Life Sciences, Grey Wolf Therapeutics, GSK, Guidepoint, IDEAYA Biosciences, Idience, Ignyta, Inc., I-Mab, ImmuneSensor Therapeutics, Inc., IMPACT Therapeutics, Institut Gustave Roussy, Intellisphere LLC, Janssen, Joint Scientific Committee for Phase I Clinical Trials (Hong Kong), Kyn Therapeutics, Kyowa Kirin, MEI pharma, Mereo BioPharma Group plc, Merck, Merit, Monte Rosa Therapeutics, Natera, Nested Therapeutics, Nexys Therapeutics, Inc., Nimbus Therapeutics, LLC, Novocure, Odyssey Therapeutics, Oregon Health & Science University, OncoSec, Ono Pharmaceutical Co. Ltd., Onxeo, PanAngium Therapeutics, PEGASCY-Group, PER, Pfizer, Piper Sandler Companies, Pliant Therapeutics, Prelude Therapeutics, ProLynx Inc., Protai Bio, Ltd., Radiopharm Theranostics, Repare Therapeutics, resTORbio, Inc., Roche, Ryvu Therapeutics SA, Sanofi, Schrödinger, Inc., Servier Pharmaceuticals, the Swiss Group for Clinical Cancer Research, Synnovation Therapeutics, Synthis Therapeutics, Inc., Tango Biosciences, Inc., TCG Crossover, Terns Pharmaceuticals, Terremoto Biosciences, Tessellate BIO, Theragnostics, Thryv Therapeutics Inc., TOLREMO therapeutics, AG, Tome Biosciences, Translational Drug Development (TD2), Trevarx Biomedical, Varian, Veeva Systems, Versant Ventures, Vibliome Therapeutics, LLC, Voronoi Inc., XinThera Inc., Zai Lab, and ZielBio; receives or has received research support from Artios Pharma, AstraZeneca, Bayer, BeiGene, BioNTech, Blueprint Medicines, Bristol Myers Squibb, Boundless Bio, the Cancer Prevention and Research Institute of Texas, Clovis Oncology, Constellation Pharmaceuticals, Cyteir Therapeutics, Eli Lilly and Company, EMD Serono, Exelixis, Forbius, F-star Therapeutics, GSK, Genentech, Gilead Sciences, Golfers Against Cancer, Haihe Biopharma, IDEAYA Biosciences, ImmuneSensor Therapeutics, Inc., Insilico Medicine, Ionis Pharmaceuticals, Ipsen, Jounce Therapeutics, Inc., Karyopharm Therapeutics, KSQ Therapeutics, Inc., Kyowa Kirin, Merck, Mirati Therapeutics, the National Cancer Institute of the National Institutes of Health, Novartis, Pfizer, Pliant Therapeutics, Prelude Therapeutics, Regeneron Pharmaceuticals, Repare Therapeutics, Ribon Therapeutics, Inc., Roche, Rubius Therapeutics, Sanofi, Scholar Rock, Seagen, Synnovation Therapeutics, Inc., Tango Biosciences Inc., Tesaro, the U.S. Department of Defense, V Foundation for Cancer Research, Vivace Therapeutics, Zenith Epigenetics, and Zentalis Pharmaceuticals; and holds stock in Seagen.
Interviews with:
Stacey A. Kenfield ScD, Epidemiologist, Professor of Urology, Epidemiology and Biostatistics, and June Chan ScD, Cancer Epidemiologist, Department of Epibiostat and Urology, University of California San Francisco, California USA.
SAN DIEGO, USA—Physical exercise keeps patients with prostate cancer alive longer, according to a combination of epidemiological and clinical study evidence emerging from research in San Francisco, California.
Intervention study findings reported at the American Association for Cancer Research (AACR) Annual Meeting in San Diego are consistent with mounting epidemiological evidence showing that regular physical exercise can help patients with advanced or metastatic prostate cancer live longer, have slower disease progression and improve their quality of life.
Stacey A. Kenfield ScD, Professor of Urology, Epidemiology and Biostatistics at the University of California San Francisco (UCSF) reported from the INTERVAL-GAP4 trial. Together with her colleague, June Chan ScD, Cancer Epidemiologist in the Department of Epibiostat and Urology at UCSF (who chaired the session on exercise for cancer patients at the AACR) she talked with the Audio Journal of Oncology about the findings and recommendations for using physical exercise as an adjunct to standard management for patients with prostate cancer.
Audio Journal of Onclogy Episode:
Stacey A. Kenfield ScD and June Chan ScD, University of California San Francisco
IN (Sarah Maxwell): There’s new evidence that exercise….. OUT: From me, Sarah Maxwell, Bye bye!” 10:28 secs
AACR ABSTRACT TITLE:
Intense exercise for survival among men with metastatic prostate cancer: 12-month feasibility results from the INTERVAL-GAP4 trial pilot site at Edith Cowan University, Australia
First Author:
Stacey A. Kenfield, UCSF – University of California San Francisco, San Francisco, CA,
Authors:
- A. Kenfield1, N. H. Hart2, J. Sison1, J. M. Chan1, K. S. Courneya3, F. Saad4, R. U. Newton5;
Institutions:
1UCSF – University of California San Francisco, San Francisco, CA, 2University of Technology Sydney, Sydney, Australia, 3University of Alberta, Edmonton, AB, Canada, 4Université de Montréal, Montréal, QC, Canada, 5Edith Cowan University, Perth, Australia
Stacey A. Kenfield, Departments of Urology and Epidemiology & Biostatistics, University of San Francisco California, San Francisco, CA
ABSTRACT
Introduction:
Men with prostate cancer undertaking moderate-to-vigorous exercise have a marked reduction of 30-60% in all-cause and cancer-related mortality based on observational studies. In 2016, the Intense Exercise for Survival among Men with Metastatic Prostate Cancer (INTERVAL-GAP4) was launched to determine if supervised exercise improves overall survival in men with metastatic prostate cancer. Here, we describe the demographic characteristics, completion rates, exercise adherence, and safety of the first 12 months of the intervention at the pilot site, Edith Cowan University in Perth, Australia.
Methods:
INTERVAL-GAP4 is a multi-center global randomized controlled phase III trial. Patients are randomly allocated (1:1) to: (intervention) a high intensity combined resistance and aerobic exercise supervised program for 1 year tapering to self-management in year 2; or (control) self-directed unsupervised exercise with print materials. Patients were stratified by site and by disease/treatment status (metastatic hormone-sensitive prostate cancer [mHSPC] or metastatic castration-resistant prostate cancer [mCRPC] and if the latter, treatment modality). The study did not meet recruitment goals and closed to further enrollment in February 2023.
Results:
240 participants were evaluated between April 2016-Feb 2023, 60 patients were consented, 52 participants were randomized, and two patients did not receive the allocation, resulting in 50 participants (27 intervention and 23 control). Main reasons for exclusion were not meeting clinical criteria (N=81), time commitment (N=24), unable to contact (N=22), not interested (N=19), and poor physical function (N=13). Median age at randomization was 72 years (IQR: 68, 77), median body mass index (BMI) was 31.7 kg/m2 (IQR: 27.5, 35.7), 94% identified as white, and time since diagnosis was 5 years (IQR: 1, 9). 13 participants (26%) had mHSPC and 37 (74%) had mCRPC. Completion rates were the following at 6 months: 84% completed surveys, 62% exercise testing, and 66% biological samples. Of 42 alive at 12 months: 85% completed surveys, 73% testing, and 73% biological samples. Median exercise adherence was 90% (IQR: 78, 97) for the first 12 months of the study. Adherence was not significantly different for those with mCRPC vs. mHSPC status. There were 10 SAEs in first 12 months; all (100%) were unrelated to the intervention.
Conclusions:
Exercise training was feasible and safe in men with metastatic prostate cancer with no difference observed in exercise session adherence by disease status. Survey completion was high, while in-person completion rates were affected by the COVID-19 pandemic. Additional analysis of the entire study population (N=145) is ongoing and will be compared with the pilot site.
ALSO:
https://ascopubs.org/doi/10.1200/GO.2023.9.Supplement_1.81
Intense exercise for survival among men with metastatic prostate cancer: 12 months feasibility results from the INTERVAL-GAP4 trial.
Background: Exercise is now considered an important therapy to ameliorate treatment side effects, improve quality of life and physical function however, causation of survival benefit and the underlying mechanisms is not yet established. In 2015, the Intense Exercise for Survival among Men with Metastatic Castrate-Resistant Prostate Cancer (INTERVAL-GAP4) – a worldwide multicentre phase III trial – was launched to determine if high-intensity combined resistance and aerobic exercise plus psychosocial support improves overall survival in men with metastatic prostate cancer. Here, while exercise delivery and follow-up assessments are still taking place in 6 different countries, we aim to examine the feasibility, exercise compliance and safety of a 12-month exercise medicine program in patients with mCRPC. Methods: Experimental design was a longitudinal analysis of attrition rates, exercise attendance and compliance metrics and programme safety over the initial 12 months of patients participating in the INTERVAL-GAP4 trial at the Edith Cowan University site in Perth, Australia. Results: 201 patients were screened for participation and 46 patients (22.9%) were randomly assigned to the two study arms. Median time since prostate cancer diagnosis was 72.0 (interquartile range (IQR): 19.5-118.5) months. Most patients were previously treated with radiotherapy (53.3%). Metastases present mostly in the lymph nodes (53.3%), followed by bones (51.1%), lungs (2.2%) and bladder (2.2%). Participants attended a total of 2,907 out of 3,744 exercise sessions scheduled, with a median exercise attendance of 78.8% (IQR: 71.6%-82.7%) per participant. Majority of sessions were performed at an RPE of 7-8 indicating “vigorous intensity” or at an RPE of 5-6 indicating “moderate intensity” (67.2%). Tolerance was moderate-to-high in most sessions (83.0%). 191 adverse events (AEs) were observed throughout the study period. A total of 136 adverse events were reported by 19 participants from the exercise group, and these were mainly disease related (n= 69, 50.7%). Most AEs were grade 1 and 2 (n= 126, 92.7%). In the control group, 55 AEs were observed, and these were mainly disease related (n= 22, 40.0%) and grade 1 and 2 (n= 51, 92.7%). The most common intervention-related adverse events experienced in the exercise group were pain (n= 6, 50.0%; i.e., back pain, bone pain, lymph node pain, and general pain). Conclusions: Patients with mCPRC can participate in high-intensity aerobic and resistance training with moderate to high attendance and tolerance. The exercise intervention appears safe with limited intervention-related adverse events experienced and mostly minor and expected. However, with only 22.9% of screened patients deemed suitable and willing, this aspect of feasibility requires attention. Clinical trial information: NCT02730338.
Robert Usher Newton: Exercise Medicine Research Institute, Edith Cowan University, Joondalup, Western Australia, Australia
Pedro Lopez
Nicolas H. Hart
Daniel Abido Galvao
Dennis R Taaffe
Timothy Dudley Clay
Charles M Ryan
Stacey A. Kenfield
Fred Saad: Division of Urology, Centre Hospitalier de l’Université de Montréal (CHUM/CRCHUM), Montreal, QC, Canada
An interview with Jonathan T. Yang MD PhD, Washington University, Seattle, USA, (Formerly of Memorial Sloan Kettering Cancer Center, New York.)
SAN DIEGO, USA—An international phase one clinical study has found that a drug known to inhibit DNA damage repair was able to boost the efficacy of radiotherapy in patients being treated for their glioblastoma.
The radiosensitizer, AZD1390, an inhibitor of ataxia telangiectasia mutated (ATM) kinase, was tested as adjunctive therapy (combined with standard radiation plus temozolomide) among 115 patients who had recurrent or newly diagnosed glioblastoma.
First author Jonathan T. Yang MD PhD, of Memorial Sloan Kettering Cancer Center in New York, reported promising efficacy to the American Association for Cancer Research Annual Meeting in San Diego, where Audio Journal of Oncology correspondent Peter Goodwin caught up with him.
Audio Journal of Oncology: IN: [Sarah MAXWELL] “A radio sensitizer drug has shown …….OUT:…..from me, Sarah Maxwell, goodbye” 10:59secs
https://www.aacr.org/about-the-aacr/newsroom/news-releases/azd1390-with-radiotherapy-shows-manageable-safety-profile-and-preliminary-efficacy-for-patients-with-glioblastoma-in-phase-i-trial/
https://clinicaltrials.gov/study/NCT03423628
Abstract: “AZD1390 With Radiotherapy Shows Manageable Safety Profile and Preliminary Efficacy for Patients with Glioblastoma in Phase I Trial”
Journal ABSTRACT:
https://www.sciencedirect.com/science/article/pii/S0360301624009799
Safety and preliminary efficacy of AZD1390 + radiation therapy (RT) for glioblastoma.)
(IMRT) with glioblastoma (GBM), the most common primary brain malignancy in adults, is an aggressive cancer with limited life expectancy. The standard of care backbone for newly diagnosed GBM is intensity-modulated radiation therapy Glioblastoma (GBM), the most common primary brain malignancy in adults, is an aggressive cancer with limited life expectancy. The standard of care backbone for newly diagnosed GBM is intensity-modulated radiation therapy (IMRT) with concomitant and adjuvant temozolomide. AZD1390, an oral, highly potent, and selective ataxia telangiectasia mutated kinase inhibitor, is designed to augment the efficacy of IMRT without exacerbating neurotoxicity. AZD1390 is optimized for blood brain barrier penetration, confirmed in a human healthy volunteer PET study (NCT03215381) and a Phase 0 study in patients (pts) with GBM (NCT05182905). This global, Phase 1, open-label study (NCT03423628) evaluates the safety and preliminary efficacy of escalating doses of AZD1390 and radiation therapy (RT) in pts with GBM and brain metastases.
Materials/Methods
Eligible adult pts received escalating once-daily AZD1390 doses following a Bayesian continual reassessment method, with IMRT 35 Gy in 10 fractions over 2 weeks (Arm A, recurrent GBM) or IMRT 60 Gy in 30 fractions over 6 weeks (Arm C, newly diagnosed, O-6-methylguanine-DNA methyltransferase unmethylated GBM). Pts in both Arms received 2 additional weeks of adjuvant AZD1390 post-IMRT. Arm B included pts with brain metastases but was closed due to low recruitment and is not reported. Primary objective was safety; secondary objectives included clinical efficacy and pharmacokinetics (PK).
Results
As of Feb 6, 2024, 115 pts have received AZD1390 (75 in Arm A; 40 in Arm C) at doses of 10–900 mg/day. PK was linear with a slightly more than dose-proportional increase and a mean terminal elimination half-life around 9–11 hours. Most patients had ≥1 treatment-emergent adverse event (AE); the most common were fatigue (51.3%), nausea (39.1%) and headache (38.3%). Grade ≥3 AZD1390-related AEs occurred in 18/115 pts (15.7%). The maximum tolerated dose was identified as 400 mg in Arm A and 300 mg in Arm C. Dose limiting toxicities included, but were not limited to, creatinine kinase elevation in Arm A and radiation skin injury in Arm C. Treatment was well tolerated, with the majority of reported AEs being low-grade. AEs led to discontinuation of AZD1390 in 13.0% of pts. The safety profile was consistent across Arms despite the different RT schedules; the most notable difference was in radiation skin injury, a reversible event, with higher frequency and severity in Arm C. At doses demonstrating target engagement in the Phase 0 study, median overall survival was 12.7 months (95% CI = 10.7, 18.9, n = 21) for Arm A and is still maturing for Arm C.
Conclusion
Concurrent AZD1390 and IMRT administration is tolerated with a manageable safety profile, at doses shown to achieve clear target engagement in the Phase 0 study. Preliminary efficacy is encouraging in Arm A. These data suggest the potential for AZD1390 to act as a radiosensitizer for the treatment of GBM. Clinical investigation is ongoing.
- Previous article in issue
- Next article in issue
Author Disclosure: J.T. Yang: Grant/research funding; AstraZeneca, Kazia Therapeutics, Debiopharm, Cantex Therapeutics. Compensation/Payment; Plus Therapeutics, Nanocan Therapeutics, Kazia Therapeutics. Stock options; Nanocan Therapeutics. P.Y. Wen: Independent Contractor; Anheart, AstraZeneca, Black Diamond, Celularity, Chimerix, Day One Bio, Genenta, GlaxoSmithKline, Kintara, Merck, Mundipharma, Novartis, Novocure, Prelude Therapeutics, Sagimet, Sapience, Servier, Symbio, Tango, Telix, VBI Vaccines. Grant/research funding; AstraZeneca, Black Diamond, Bristol Myers Squibb, Chimerix. B.S. Imber: Grant/research funding; AstraZeneca. Honoraria; GT Medical Technologies, Telix Pharmaceuticals. J. Drappatz: Grant/research funding; Novocure, Servier, Novartis. Copyright/Patent/License/Royalty; Elsevier, Wolters Kluwer. Stock; Pfizer, GlaxoSmithKline, Gilead. R. Jena: None. D. Forst: Grant/research funding; American Society of Clinical Oncology. Stock; Eli Lilly. A. Zukas: None. S.C. Short: None. C. Fan: Stock; AstraZeneca. W. Trigg: Stock; AstraZeneca. A. Milner: None. U. Polanska: Stock; AstraZeneca. C. Glover: Stock; AstraZeneca. Stock options; AstraZeneca. C. Stavraka: Stock; AstraZeneca. D. Dalal: Stock; AstraZeneca. D. Karanovic: None. A. Chalmers: Grant/research funding; AstraZeneca. Honoraria; AstraZeneca.
MORE:
PRESS RELEASE:
AZD1390 With Radiotherapy Shows Manageable Safety Profile and Preliminary Efficacy for Patients with Glioblastoma in Phase I TrialSAN DIEGO – AZD1390, an ataxia telangiectasia mutant (ATM) kinase inhibitor, demonstrated a manageable safety profile in both recurrent and newly diagnosed glioblastoma (GBM) patients when given in combination with standard-of-care radiotherapy and showed preliminary efficacy in recurrent GBM patients, according to results from a global phase I trial presented at the American Association for Cancer Research (AACR) Annual Meeting 2024, held April 5-10.“Glioblastoma is a lethal cancer with the majority of patients not surviving past two years from diagnosis,” said Jonathan T. Yang, MD, PhD of Memorial Sloan Kettering Cancer Center, who presented the results of the trial. “Despite efforts to improve survival, the current standard of care continues to be a backbone of radiotherapy with or without temozolomide [Temodar] without much innovation in the past two decades. This context highlights both the urgent need to develop new medicines and the historical challenges of developing novel therapeutics for this devastating disease.”Intensity-modulated radiation therapy (IMRT), which is the standard of care in newly diagnosed GBM patients, causes the death of cancer cells by damaging the DNA inside of the cell. But the ATM cell signaling pathway is activated to help repair the DNA double-strand breaks (DSBs) caused by radiation therapy, thus impeding its effectiveness. An ATM inhibitor prevents the repair of DSBs, thereby enhancing the cancer-killing effect of radiation therapy, Yang said.GBM accounts for approximately 50% of primary malignant brain tumors. One reason brain tumors have been difficult to treat is because the blood-brain barrier prevents some therapies from penetrating into the brain and reaching the cancers they aim to treat. Because of this challenge, AZD1390 was designed to penetrate the blood-brain barrier and a healthy volunteer study recently showed that AZD1390 crossed through an intact barrier. Other pre-clinical experiments demonstrated the potential antitumor effects of AZD1390 without exacerbating IMRT toxicity in surrounding areas by not causing harm to normal, healthy brain tissue.Yang and his colleagues assessed the safety, tolerability, early efficacy, and maximum tolerated dose of AZD1390 with IMRT in humans. As of February 2024, 115 patients were given AZD1390 in the phase I trial, including 75 patients with recurrent GBM in Arm A and 36 patients with newly diagnosed, MGMT unmethylated GBM in Arm C. In both Arms, patients received escalating once-daily doses of AZD1390; patients in Arm A were given 35 Gy of IMRT in 10 fractions over two weeks while those in Arm C were given 60 Gy of IMRT in 30 fractions over six weeks. Additionally, following the completion of IMRT, patients were given adjuvant AZD1390 for two weeks.Out of the 115 patients, 18 (15.7%) experienced an AZD1390-related adverse event (AE) of a grade 3 or 4; there were no grade 5 treatment-related AEs. Additionally, 4.3% of patients discontinued AZD1390 treatment due to an AE related to AZD1390 only.“Most adverse effects experienced by patients during the study were low grade, readily manageable, and reversible in nature,” Yang said.
AZD1390 With Radiotherapy Shows Manageable Safety Profile and Preliminary Efficacy for Patients with Glioblastoma in Phase I TrialPage 2 of 3Patients in Arm C experienced a higher frequency and severity of radiation-related skin injury due to longer exposure to radiation, and most instances were easily managed and fully reversed following treatment with topical steroids and moisturizers, Yang said.The researchers identified 400 mg in Arm A and 300 mg in Arm C as the maximum tolerated doses. While Yang said they are still collecting efficacy data in both arms,. Prior studies have shown the current standard of care leads to an OS of 6 to 10 months. The OS data forArm C is still maturing.“Drug development in GBM is generally challenging due to the rarity of the disease and lack of robust early clinical indicators of efficacy,” Yang said. “If the preliminary efficacy benefit observed in this trial is proven in a pivotal study, it would be a critical, biologically supported approach to address the high unmet need in GBM.”Yang said the planning for the next phase of development is currently underway.Limitations of this study include the single-arm and open-label nature of the study with a small sample size.This study was funded by AstraZeneca. Yang also reports having received past funding from Kazia Therapeutics, Plus Therapeutics, Debiopharm, Cantex Pharmaceuticals, and Biocept. He has also worked as an independent contractor for Galera Therapeutics, Nanocan Therapeutics, Kazia Therapeutics, Plus Therapeutics, and AstraZeneca. He has stock options in Nanocan Therapeutics.AbstractSession Title: Novel Agents and Emerging Therapeutic Strategies Location: Hall GH – Ground Level – Convention CenterSession Time:Tuesday, April 9, 2024, 2:30 pm – 4:30 pm Presentation CT043Number:Poster BoardNumber:Publishing Safety and preliminary efficacy of AZD1390 + radiation therapy (RT) for glioblastoma Title: (GBM)J. T. Yang1, P. Wen2, B. S. Imber1, J. Drappatz3, R. Jena4, D. Forst5, A. Zukas6, S. C. Short7, C. Fan8, W. Trigg9, A. Milner9, U. Polanska10, C. Glover9, C. Stavraka9, D. Dalal11, D. Karanovic8, A. J. Chalmers12;1Memorial Sloan Kettering Cancer Center, New York, NY, 2Center for Neuro-oncology, Dana-Farber Cancer Institute, Boston, MA, 3University of Pittsburgh Medical Center,Author Block: Pittsburgh, PA, 4University of Cambridge, Cambridge, United Kingdom, 5Massachusetts General Hospital, Boston, MA, 6Medical University of South Carolina, Charleston,SC, 7Leeds Institute of Medical Research at St. James’s, Leeds, UnitedKingdom, 8AstraZeneca, Gaithersburg, MD, 9AstraZeneca, Cambridge, United Kingdom, 10AstraZeneca, Warsaw, Poland, 11AstraZeneca, New York, NY, 12School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdoman encouraging median overallsurvival (OS) of 12.7 months was observed in Arm A patients at doses demonstrating target engagementAbstract Body:Objective:GBM, the most common primary brain malignancy in adults, is an aggressive cancer with limited life expectancy. The standard of care backbone for newly diagnosed GBM is intensity-modulated RT (IMRT) with concomitant and adjuvant temozolomide. AZD1390, an oral, highly potent, and selective ataxia telangiectasia mutated kinase inhibitor, is designed to augment the efficacy of IMRT without exacerbating neurotoxicity. AZD1390 is optimized for blood brain barrier penetration, confirmed in a human healthy volunteer PET study (NCT03215381) and a Phase 0 study in patients (pts) with GBM
AZD1390 With Radiotherapy Shows Manageable Safety Profile and Preliminary Efficacy for Patients with Glioblastoma in Phase I TrialPage 3 of 3(NCT05182905). This global, Phase 1, open-label study (NCT03423628) evaluates the safety and preliminary efficacy of escalating doses of AZD1390 and RT in pts with brain malignancies.Methods: Eligible adult pts received escalating once-daily AZD1390 doses following a Bayesian continual reassessment method, with IMRT 35 Gy in 10 fractions over 2 weeks (Arm A, recurrent GBM) or IMRT 60 Gy in 30 fractions over 6 weeks (Arm C, newly diagnosed, MGMT unmethylated GBM). Pts in both Arms received 2 additional weeks of adjuvant AZD1390 post-IMRT. Arm B included pts with brain metastases but was closed due to low recruitment and is not reported. Primary objective was safety; secondary objectives included clinical efficacy and pharmacokinetics (PK).Results: As of Nov 15, 2023, 111 pts have received AZD1390 (75 in Arm A; 36 in Arm C) at doses of 10-900 mg/day. PK was linear with a slightly more than dose-proportional increase and a mean terminal elimination half-life around 9-11 hours. Most patients had ≥1 treatment-emergent adverse event (AE); the most common were fatigue (53.2%), headache (38.7%) and nausea (38.7%). Grade ≥3 treatment-related AEs occurred in 18/111 pts (16.2%). The maximum tolerated dose was identified as 400 mg in Arm A and 300 mg in Arm C. Dose limiting toxicities included, but were not limited to, creatinine kinase elevation in Arm A and radiation skin injury in Arm C. Treatment was well tolerated, with the majority of reported AEs being low-grade. AEs led to discontinuation of AZD1390 in 12.6% of pts. The safety profile was consistent across Arms despite the different RT schedules; the most notable difference was in radiation skin injury, a reversible event, with higher frequency and severity in Arm C. At doses demonstrating target engagement in the Phase 0 study, median overall survival was 12.7 months (95% CI, 10.7, 18.9, n=21) for Arm A and is still maturing for Arm C.Conclusions:Concurrent AZD1390 and IMRT administration is tolerated with a manageable safety profile, including at doses shown to achieve clear target engagement in the Phase 0 study. Preliminary efficacy is encouraging in Arm A. These data suggest the potential for AZD1390 to act as a radiosensitizer for the treatment of GBM. Clinical investigation is ongoing.
An interview with:
Heather McArthur MD MPH, Clinical Director Breast Cancer, Komen Distinguished Chair Clinical Breast Research, University of Texas Southwestern Medical Center, Dallas TX
MILAN, Italy—Adjuvant therapy with a checkpoint inhibitor did not benefit patients with triple negative breast cancer in a big new study reported to the 14th European Breast Cancer Conference in Milan, Italy.
Heather McArthur MD MPH, Clinical Director of Breast Cancer and Komen Distinguished Chair in Clinical Breast Research at the University of Texas Southwestern Medical Center, Dallas TX, told the conference that the ALEXANDRA/IMpassion030 phase 3 trial failed to show a survival benefit when adjuvant atezolizumab was added to standard therapy. In Milan, she discussed the findings with Audio Journal of Oncology reporter Peter Goodwin.
Heather McArthur MD MPH:
IN: [SARAH MAXWELL] Patients with triple negative ,,OUT: …from me, Sarah Maxwell, good-bye. 10;06secs
ABSTRACT:
14th European Breast Cancer Conference Abstract no: 4
Abstract no: 1LBA, “Adjuvant chemotherapy with or without atezolizumab for stage II and III triple-negative breast cancer: final analysis of the ALEXANDRA/IMpassion030 phase 3 trial”
EBCC 2024, Wednesday 20 March, Young Investigator Innovation Award and oral abstract session, 11:00-12:55 hrs CET,.
https://cm.eortc.org/cmPortal/Searchable/ebcc14/config/Normal/#!sessiondetails/0000107210_0
https://www.ejcancer.com/article/S0959-8049(24)00177-1/fulltext
MORE:
PRESS RELEASE
Embargoed: 00.01 hrs CET, Wednesday 20 March 2024
Addition of atezolizumab to chemotherapy after surgery does not improve survival for triple negative breast cancer
— Final analysis of the ALEXANDRA/IMpassion030 phase 3 trial —
Milan, Italy: Patients with triple-negative breast cancer do not benefit from the addition of atezolizumab to their post-surgery chemotherapy treatment, according to the results of a large phase 3 clinical trial presented at the 14th European Breast Cancer Conference.
Triple negative breast cancer, so-called because the cancer cells are not fuelled by oestrogen, progesterone or the HER2 protein, is harder to treat and more likely to spread to other parts of the body.
Previous research has suggested that adding an immunotherapy treatment to chemotherapy before surgery can improve survival for this groups of patients. The new results show that including atezolizumab, a type of immunotherapy, with chemotherapy after surgery does not bring the same benefits.
The ALEXANDRA/IMpassion030 study is a phase 3 clinical trial that included 2199 people from 31 different countries with stage two or three triple negative breast cancer. Following surgery to remove their cancer, half of the patients were randomly assigned to be treated with chemotherapy plus atezolizumab, with the other half treated with chemotherapy.
The final analysis of the trial was presented by Dr Heather McArthur, an Associate Professor in the Department of Internal Medicine and Clinical Director of the Breast Cancer Program at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center in Dallas, Texas, USA.
She said: “We know from a previous trial that including the immunotherapy treatment atezolizumab with chemotherapy prior to surgery is beneficial for patients with triple-negative breast cancer. The ALEXANDRA/IMpassion030 trial is the first study to look at the role of chemotherapy with or without atezolizumab post-surgery for early-stage triple-negative breast cancer.”
Patients have now been monitored for an average of 32 months. Researchers found no improvement for patients treated with atezolizumab after surgery compared to those not treated with atezolizumab in terms of survival and remaining free of cancer. Among the patients taking atezolizumab there were 141 (12.8%) who had a recurrence or died. Among patients not taking atezolizumab, there were 125 (11.4%) who had a recurrence or died. This equates to a hazard ratio of 1.11 for patients taking atezolizumab.
Researchers also found no benefit when looking at different sub-groups, such as patients whose cancer had spread to the lymph nodes and patients with PD-L1 positive cancer, which is used as a marker of cancers that are more likely to respond to immunotherapy.
Dr McArthur said: “This is a large international clinical trial looking at treatment for patients with triple-negative breast cancer. The results of this final analysis are important because they show that including the immunotherapy drug atezolizumab alongside chemotherapy does not help when it’s given to patients following surgery. By extension, this also highlights the importance of treating triple-negative breast cancer with chemotherapy and immunotherapy prior to surgery, as per the current standard of care.”
The final analysis also showed that the safety of atezolizumab, in terms of unwanted side effects, was consistent with other trials of the treatment. Among the patients treated with atezolizumab and chemotherapy, 54.3% experienced serious side effects. Among those treated with chemotherapy alone, 44.1% experienced serious side effects.
The co-chair of the 14th European Breast Cancer Conference is Dr Fiorita Poulakaki, Head of the Breast surgery Department at Athens Medical Center Hospital, Greece, and Vice President of Europa Donna, the European Breast Cancer Coalition, and was not involved with the research. She commented: “We always hope that testing new treatment approaches will improve patients’ outcomes. However, it’s just as important to know when a new treatment added to one that is already in use one is not beneficial, as in this case, to make sure patients aren’t subjected to a treatment that doesn’t work and may cause more side effects.
“The results of this final analysis show that chemotherapy with atezolizumab after surgery does not improve disease-free survival for early-stage triple-negative breast cancer. This research therefore highlights the importance of the current approach of treating triple negative breast cancer with chemotherapy and immunotherapy to shrink the tumour before surgery. This is vital information for surgeons and medical oncologists who treat patients with this aggressive type of cancer.”
Abstract no: 1LBA, “Adjuvant chemotherapy with or without atezolizumab for stage II and III triple-negative breast cancer: final analysis of the ALEXANDRA/IMpassion030 phase 3 trial”, Young Investigator Innovation Award and Oral abstracts, Wednesday 20 March, 11.00-12.55, Silver room.
https://cm.eortc.org/cmPortal/Searchable/ebcc14/config/Normal/#!sessiondetails/0000107210_0
1LBA LBA Oral – Adjuvant chemotherapy with or without atezolizumab for stage II and III triple-negative breast cancer: final analysis of the ALEXANDRA/ IMpassion030 phase 3 trial
- McArthur1∙ A. Bailey2 ∙ S. Saji3 ∙ … ∙ M. Piccart18 ∙ M. Ignatiadis5 ∙ R. Gelber19 … Show more
Affiliations & NotesArticle Info
Background: Early-stage triple negative breast cancer (TNBC) is associated with a high risk of distant relapse. ALEXANDRA/IMpassion030 is a global, prospective, randomized, open-label, phase 3 trial that investigated the efficacy and safety of adjuvant atezolizumab (atezo) plus standard anthracycline/taxane chemo (atezo+chemo) versus standard anthracycline/ taxane chemo (chemo alone) in early-stage TNBC.
Material and Methods: In ALEXANDRA/IMpassion030 (NCT03498716) patients with resected stage II-III TNBC, confirmed by central pathology review, were randomized 1:1 to receive adjuvant chemo with or without atezo. Patients were stratified by type of surgery (breast conserving vs mastectomy), axillary nodal status (0 vs 1-3 vs ≥4 nodes), and centrally assessed PD-L1 status (IC0 vs IC1/2/3). Adjuvant chemo consisted of weekly paclitaxel 80 mg/m for 12 weeks followed by dose-dense anthracycline (epirubicin 90 mg/m2 or doxorubicin 60 mg/m2) and cyclophosphamide 600 mg/m2 for 4 doses every 2 weeks given concomitantly with atezo 840 mg every 2 weeks followed by maintenance atezo 1200 mg every 3 weeks until completion of 1 year of atezo or the same chemo regimen alone. The primary endpoint was invasive disease-free survival (iDFS) in the intention-to-treat population (ITT). Recruitment stopped after 2199 of the planned 2300 patients were enrolled (1101 atezo+chemo and 1098 chemo alone) on the recommendation of the independent data monitoring committee (IDMC). At the Interim Analysis (IA) with ∼25 months median follow-up and 239 iDFS events the hazard ratio (HR) for iDFS (primary endpoint) crossed the pre-specified futility boundary. The final analysis with ∼32 months median follow-up and 266 iDFS events is reported here.
Results: At the final analysis, the HRs remained stable compared to the IA for iDFS at 1.11 (0.87, 1.42) and for secondary endpoints: iDFS in the PDL1+ subset 1.00 (0.73, 1.35), iDFS in the node-positive subset 1.32 (0.97, 1.8), and overall survival 1.23 (0.87, 1.73) for the 2199 patients in the ITT population. At the final analysis, 2177 (99%) were safety-evaluable, 1567 (71.3%) had PD-L1 positive disease and 1067 (48.5%) had node-positive disease. The incidence of grade≥3 treatment related adverse events remained stable with 54.3% in the atezo+chemo arm vs 44.1% in the chemo alone arm.
Conclusions: At the final analysis, the addition of atezo to adjuvant anthracycline- and taxane-based chemo did not improve iDFS in the ITT population of stage II-III TNBC or in any of the subgroups interrogated. Safety data remain consistent with the known profile of atezo in early TNBC.
Conflict of interest: Advisory Board: Dr. McArthur has consulted for Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Pfizer, Puma, Spectrum Pharmaceuticals, Syndax Pharmaceuticals, Peregrine, Calithera, Daiichi-Sankyo, Seattle Genetics, AstraZeneca, Gilead, Crown Bioscience, and TapImmune.
Corporate-sponsored Research: Dr. McArthur has research supported by Bristol-Myers Squibb MedImmune, LLC/AstraZeneca BTG and Merck.
1UTSW, Internal Medicine, Dallas, USA;
2Frontier Science, Inverness-Shire, United Kingdom;
3Fukushima Medical University, School of Medicine, Fukushima, Japan;
4Breast International Group, Brussels, Belgium;
5Institut Jules Bordet, Brussels, Belgium;
6Dana-Farber Cancer Institute, Boston, USA;
7Roche, Basel, Switzerland;
8Lviv State Oncology Regional Treatment and Diagnostic Center, Department of Chemotherapy, Lviv, Ukraine;
9Soonchunhyang University, Department of Oncology, Dongnam, South Korea;
10Clinique Tivoli Ducos, Medical Oncology, Bordeaux, France;
11Hospital Clinico Universitario Virgen de la Arrixaca, El Palmar, Spain;
12Frontier Science, Kingussie, United Kingdom;
13Omsk Clinical Oncology Dispensary, Department of Oncology, Omsk, Russia;
14Kanagawa Cancer Center, Department of Breast Surgery, Nakao, Japan;
15Genentech, San Francisco, USA;
16Fudan University Shanghai Cancer Center, Department of Breast Surgery, Shanghai, China;
17University of Milan, European Institute of Oncology, Milan, Italy;
18Institut Jules Bordet, Boston, USA;
19Dana-Farber Cancer Institute, Cancer Institute, Boston, USA
An interview with: Stefan Paepke MD, Interdisciplinary Breast Centre, Technical University of Munich, Germany, recorded at the 14th European Breast Cancer Conference, Milan, Italy.
MILAN, Italy—Women who need surgical implants after their mastectomy for breast cancer could now benefit from mesh-supported prosthetics that bring high rates of satisfaction and psychosocial well-being, with low complication rates. That’s according to findings from German PRO-Pocket-Trial, reported at the 14th European Breast Cancer Conference in Milan.
Study patients who had the new “tetanized” mesh-pocket-supported implants positioned by means of a “pre-pectoral” procedure found the technique prevented the unnatural breast mobility after reconstruction sometimes called: “jumping breasts”, while giving a better cosmetic appearance.
At the conference, our reporter Peter Goodwin talked with lead author of the study: Stefan Paepke MD, from the Interdisciplinary Breast Centre at the Technical University of Munich, in Germany
Stefan Paepke MD PODCAST
IN (Sarah MAXWELL): There’s good news for women ….OUT (Peter GOODWIN): European Breast Cancer Conference.I’m Peter Goodwin 10:48 secs
EBCC ABSTRACT:
“Mesh-Pocket Supported Prepectoral Direct-to-Implant Breast Reconstruction: Preliminary Results of a Prospective Analysis”
https://www.ejcancer.com/article/S0959-8049(22)01378-8/fulltext
Background:
Safety and breast aesthetics of direct-to-implant techniques are well recognized. Pre-pectoral techniques add a new dimension supported by the next generation of titanized mesh-pockets.
Material and Method:
A prospective international, multicentre observational investigation (PRO-Pocket-Trial CLINICALTRIALS.GOV NCT03868514 and DRKS00016673) is performed in 12 clinical centres in Germany and Austria to obtain data regarding patient reported outcome, cosmetic outcome and complications after TiLOOP® Bra Pocket supported prepectoral breast reconstruction up to the 24 months Follow-Up.
Results:
From 06/2019 until 02/2021, 313 patients with TiLOOP® Bra Pocket supported breast reconstructions were included. Age of the patients was between 23 and 80 years. The mean of the BMI was 24.5 ± 4.5 kg/m2. The most frequent indication for surgery was invasive ductal carcinoma followed by increased breast cancer risk. Unilateral surgery was performed in about 40%. The most frequent incision technique was an inframammary incision followed by inverted T-technique and hockey stick incision. About 70% of the breast implants were of anatomic shape; textured surface was also reported in about 75% of the reconstructions. None of the reported complications was unexpected; currently, 1 dysesthesia, 6 wound healing disturbances, 11 hematomas, 4 capsular fibrosis, 5 infections, 6 necrosis, and 15 seromas are documented.
Discussion:
Use of TiLOOP® Bra Pocket enables a new standard of prepectoral reconstructive techniques preserving the natural anatomy, thereby avoiding adverse effects associated with submuscular reconstruction, minimizing postoperative pain, risk of bleeding and the lack of animation deformity like “jumping breast phenomenon.” Pocket-supported reconstructive techniques become more valuable in times of changing to implants with smooth surface due to the excellent stabilization of implant position.
MORE:
Post Market Clinical Follow Up to “Patient Reported Outcome” Using a Titanised Polypropylene Mesh (TiLOOP® Bra Pocket) (PRO-Pocket)
Brief Summary:“PRO-Pocket” – International prospective multicentre Post Market Clinical Follow Up to “Patient reported outcome” in primary or secondary breast reconstruction after mastectomy using a titanised polypropylene mesh (TiLOOP® Bra Pocket)
This international, multicentre, non-randomised, observational clinical device investigation will be performed to obtain post market information on TiLOOP® Bra Pocket surgical meshes for a period of up to two years. In particular, on patient reported satisfaction (BreastQTM), cosmetic outcome and the rate of complications.The objective of the clinical Investigation is to establish the efficacy and safety of the TiLOOP® Bra Pocket.The Investigation will be performed in ten clinical centres in Germany and Austria.ObservationalActual Enrollment : 313 participantsObservational Model: CohortTime Perspective: ProspectiveOfficial Title: “PRO-Pocket” – International Prospective Multicenter Post Market Clinical Follow Up to “Patient Reported Outcome” in Primary or Secondary Breast Reconstruction After Mastectomy Using a Titanised Polypropylene Mesh (TiLOOP® Bra Pocket)Actual Study Start Date : July 4, 2019Actual Primary Completion Date : June 22, 2022Actual Study Completion Date : November 15, 2023
Primary or secondary breast reconstruction following mastectomy with titanised polypropylene mesh TiLOOP® Bra Pocket
Primary Outcome Measures :Quality of Life – Patient reported outcome [ Time Frame: 12 months after study treatment ]The primary endpoint is defined as the change of the four BreastQ domain scores before study treatment compared to twelve months after study treatment. The BreastQ questionnaire yields a domain score in the range from zero to 100. Wheras a score of 100 is the best score. The study hypothesis is that the patient’s QoL after the study intervention treatment is not worse than the QoL prior to the intervention studyAges Eligible for Study: 18 Years and older (Adult, Older Adult)Sexes Eligible for Study: FemaleAccepts Healthy Volunteers: YesSampling Method: Non-Probability SampleStudy PopulationWomen with indicated implant based breast reconstruction after mastectomy.CriteriaInclusion Criteria:Age [≥ 18]Indications of breast reconstruction: histologically confirmed breast cancer, precancerous lesions (DCIS, LCIS), mutation carrier with increased breast cancer risk, strong family history (lifetime risk > 15%)The patient is capable to realise the nature, aims and possible consequences of the clinical trial (MPG §20.2.1)Patient information has been provided and all written consents of the patient are availableExclusion Criteria:Metastatic breast cancerPatient with known contraindications against mesh-assisted or plastic-reconstructive breast surgery according to the instruction for usePatient is kept in an institution under judicial or official orders (MPG §20.3)Participate in another operative clinical trial, if it relates to the area of reconstructive breast surgery and/or influences the primary endpoint of the clinical trialContacts and LocationsGo to sections
Information from the National Library of MedicineTo learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03868514
LocationsAustriaUniversitätsklinik für Frauenheilkunde, Allgemeines Krankenhaus der Stadt WienVienna, Austria, 1090GermanyVivantes Klinikum Am UrbanBerlin, Germany, 10967DRK Kliniken WestendBerlin, Germany, 14050Universitätsklinikum BonnBonn, Germany, 53127Kliniken Essen Mitte; Evang. Huyssens-StiftungEssen, Germany, 45136Agaplesion Markus KrankenhausFrankfurt, Germany, 60431Universitätsmedizin GreifswaldGreifswald, Germany, 17475Universitätsklinikum HeidelbergHeidelberg, Germany, 69120Rotkreuzklinikum MünchenMunich, Germany, 80637Klinikum rechts der Isar der Technischen Universität MünchenMunich, Germany, 81675Universitätsklinikum UlmUlm, Germany, 89075
GRN Klinik WeinheimWeinheim, Germanytreatment . The following four domains are relavant: Satisfaction with breasts, Psychosocial well-being, Physical well-being:chest and Sexual well-being.
Secondary Outcome Measures :Quality of Life – Patient reported outcome [ Time Frame: 6 and 24 months after study treatment ]The change of the four BreastQ domain scores before study treatment compared to six months and 24 months after study treamtment.
Complication rate [ Time Frame: 6, 12 and 24 months after study treatment ]The number and rate of occurrence of adverse events is reported as a secondary endpoint along with a tabulation of the types of adverse events (6, 12 and 24 months after study treatment).
Cosmetic outcome [ Time Frame: 6, 12 and 24 months after study treatment ]The cosmetic outcome is assessed based on photographs 6, 12 and 24 months after study treatment by descriptive statistics (an independent expert, the physician in charge and the patient assess the cosmetic outcome).
An interview with Sophie Bosma MD PhD, from The Netherlands Cancer Institute, Amsterdam recorded at the 14th European Breast Cancer Conference in Milan.
MILAN, Italy—The optimal radiation boost dose to protect young patients with early breast cancer has been investigated with ten years of follow up in the “Young Boost trial” conducted in the Netherlands. The study randomized between giving patients a low radiation dose as a boost to their standard radiotherapy or a high dose.
At the 14th European Breast Cancer Conference held in Milan Radiation Oncologist Sophie Bosma MD PhD, from The Netherlands Cancer Institute in Amsterdam reported that a low dose had comparable efficacy with lower toxicity and should now be recommended. In Milan she talked about the findings with Audio Journal of Oncology reporter Peter Goodwin.
AUDIO JOURNAL OF ONCOLOG, with: Sophie Bosma MD PhD, Netherlands Cancer Institute
IN (Goodwin): “For your young patients ….. OUT: …..for the Audio Journal of Oncology I’m Peter Goodwin 8:46secs
SEE:
00180-1/fulltext
MORE:
News release:
Low-dose radiotherapy boost helps prevent local recurrence with better cosmetic outcomes in young breast cancer patients
The researchers conclude that the ‘benefit does not justify the increased impact on cosmetic outcomes’.
Bosma said: “In both groups local recurrence rates were very low and much better than expected. Although we did find a difference between the two groups in terms of the recurrence rate, this was a small difference which must be weighed against the increase in side effects, such as fibrosis.
“Knowing the long-term impact of a treatment on cancer control as well as on unwanted side-effects is crucial in helping individual patients get the best possible treatment.”
Michail Ignatiadis MD PhD from the Institut Jules Bordet in Brussels, Belgium, Chair of the 14th European Breast Cancer Conference, who was not involved in the research, said: “Radiotherapy plays an important role in breast cancer treatment, especially in young women where there is a higher risk of the breast cancer returning. This important study provides critical information for the optimal boost radiotherapy dose for achieving local control without compromising the cosmetic outcome.”
Abstract no: 4LBA,
“Young boost randomized phase III trial of high vs low boost radiation in young breast cancer patients: 10-year results”,
https://cm.eortc.org/cmPortal/Searchable/ebcc14/config/Normal#!sessiondetails/0000107220_0
4LBA LBA Mini Oral – Young boost randomized phase III trial of high vs low boost radiation in young breast cancer patients: 10-year results
European Journal of Cancer:
https://www.ejcancer.com/article/S0959-8049(24)00180-1/fulltext
Sophie Bosma et al:
1The Netherlands Cancer Institute, Radiation oncology, Amsterdam – HollandPTC- Delft, The Netherlands;
2Erasmus MC Cancer Institute, Statistics, Rotterdam, The Netherlands;
3The Netherlands Cancer Institute, Radiation oncology, Amsterdam, The Netherlands;
4Institute Curie, Radiation oncology, Paris, France;
5Catharina Hospital, Radiation oncology, Eindhoven, The Netherlands;
6University Medical Center Groningen, Radiation oncology, Groningen, The Netherlands;
7The Netherlands Cancer Institute, Surgical Oncology, Amsterdam, The Netherlands;
8Institute Verbeeten, Radiation oncology, Tilburg, The Netherlands;
9Radboud University Medical Center, Radiation Oncology, Nijmegen, The Netherlands;
10Radiotherapiegroep, Radiation oncology, Arnhem, The Netherlands;
11Amsterdam UMC, Pathology, Amsterdam, The Netherlands;
12Iridium Netwerk, Antwerp, Belgium, University of Antwerp, Faculty of Medicine and Health Sciences, Radiation oncology, Antwerp, Belgium;
13MAASTRO-GROW School for Oncology and Developmental Biology- Maastricht University Medical Centre, Radiation oncology, Maastricht, The Netherlands
Background: An extra radiation boost dose to the primary tumour bed in addition to whole-breast irradiation (WBI) reduces local recurrence (LR) risk after lumpectomy. As young age is a risk factor for LR, the young boost trial (NCT00212121) investigated whether an increased boost dose could improve local control in young patients. Here, we present the results of the 10-year primary analysis.
Material and Methods: Between 2004 and 2011, patients≤50 yrs with pT1-2, pN0-2a invasive breast cancer after a microscopically complete excision (focally involved margins were allowed) were randomly assigned to receive a boost of 26 Gy (high) or 16 Gy (low) to the tumour bed. Patients were stratified by age, tumour size, lymph node involvement, interstitial/ external boost, and institution. Primary endpoint was local control at 10 years. The revised design (2008) assumed a 3.5% difference in local control at 10 years (from 92 to 95%; power 90%; two-sided significance level α of 5%). All new tumours in the ipsilateral breast were counted as LR. We used competing risk analysis with death as competing risk.
Results: In total, 2421 patients were randomized in 32 centres in the Netherlands, France, and Germany. 1211 patients were assigned to a high and 1210 patients to a low boost. Median follow-up was 11.7 years. Baseline characteristics were well-balanced between both two arms. Median age at diagnosis was 45 years (IQR 41-48), the median pathological diameter was 15 mm (IQR 1-80), and 70% was pN0. Tumours were grade 2 or 3 in.82 % and subtype was 67% ER+HER2-, 20% TNBC, and 13% HER2pos. 65% was treated with a sequential boost; 35% with a simultaneously integrated boost. Boost techniques consisted of X-ray beams in 75%, electrons in 20%, 1% interstitial boost and 4% others. Systemic treatment was given to 82% of patients. In total, 109 local recurrences have occurred (61 low boost, 48 high boost). LR was the first event for 42 patients in the low boost and 23 patients in the high boost arm. The 10-year LR-rate for patients treated with a low boost was 4,4% (95% CI 3,4-5,8) versus 2,8% (95% CI 1,9-3,9) in patients treated with a high boost, HR 0.61 (95% 0.39-0.96), p 0.032. Factors significantly associated with LR in multivariable analysis were boost dose, final margin status, subtype, and the use of chemotherapy. The cumulative incidence of marked or moderate fibrosis in the boost area was 27% patients treated with a low boost vs 48% patients treated with a high boost.
Conclusions: Local control in young breast cancer patients was excellent. The primary endpoint that a high radiation boost after whole-breast irradiation improves local control by at least 3.5% was not met. The small statistically significant benefit does not justify the increased impact on cosmetic outcomes.
An interview with: Adri Voogd PhD, Associate Professor of Clinical Epidemiology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
MILAN, Italy—Although outcomes following breast conserving surgery (with or without radiotherapy) for ductal carcinoma in situ (DCIS) are excellent, it is still not clear which cases would never have progressed in all events.
A 30-year-long population-based epidemiology study reported to the 14th European Breast Cancer conference held in Milan has now brought some granular detailed data showing that breast conserving therapy had become increasingly effective in preventing the emergence of breast cancer over the long term, but that clinical judgement is still needed to balance the benefits against the risks and costs of intervening.
The population-based, Netherlands Cancer Registry retrospective cohort study of 25,719 women with DCIS diagnosed from 1989 up to 2021 (all of whom were treated with standard conservative therapy) found there were both successes and limitations with the current standard of care for DCIS.
Surprisingly, long-term risk appeared to have been unrelated to tumor grade. Also: despite a continuing improvement in outcomes during this time period, the investigators concluded that specific molecular predictors of outcome still needed to be identified to distinguish intrinsically low-risk tumors (that did not require even conservative therapy) from those that carry a higher risk, and are highly likely to benefit from breast conserving surgery and radiotherapy.
After reporting the study findings in Milan, study author Adri Voogd PhD, Associate Professor of Clinical Epidemiology in the Faculty of Health, Medicine and Life Sciences at Maastricht University, Maastricht, The Netherlands, talked with Peter Goodwin.
Adri Voogd INTERVIEW
IN (GOODWIN): “Breast conserving therpy was ………” OUT: “….. for the Audio Journal of Oncology, I’m Peter Goodwin.” 15:53 secs
2024 EBCC, Milan Mini Oral session, Abstract 13:
https://event.eortc.org/ebcc14/wp-content/uploads/sites/31/2024/03/EBCC14-Abstract-Book.pdf
https://www.nature.com/articles/s41416-024-02785-6
https://www.ejcancer.com/article/S0959-8049(24)00209-0/fulltext
Abstract:
“Invasive recurrence after breast conserving treatment of ductal carcinoma in situ of the breast in the Netherlands between 1989 and 2021: Time trends and the association with tumour grade”
Authors:
- O’Leary1, L. Duijm2, L. Boersma3, M. van der Sangen4, L. de Munck5, J. Wesseling6, R.J. Schipper7, A. Voogd1. 1Maastricht University, Department of Epidemiology, Maastricht, Netherlands; 2Canisius Wilhelmina Hospital, Department of Radiology, Nijmegen, Netherlands; 3Maastricht University Medical Centre, Department of Radiation Oncology MAASTRO, Maastricht, Netherlands; 4Catharina Hospital, Department of Radiation Oncology, Eindhoven, Netherlands; 5Netherlands Comprehensive Cancer Organization, Department of Research and Development, Utrecht, Netherlands; 6The Netherlands Cancer Institute, Department of Pathology, Amsterdam, Netherlands; 7Catharina Hospital, Department of Surgery, Eindhoven, Netherlands
Background:
The aim of this study was to provide insight in trends and up-to- date figures of the risk of invasive ipsilateral breast cancer (iIBC) after breast conserving surgery (BCS) of ductal carcinoma in situ (DCIS) with or without adjuvant radiotherapy (RT) and to compare these figures with the risk to develop an invasive breast cancer in the contralateral breast (iCBC). A second aim was to analyze the association between DCIS grade and the risk of iIBC and to compare DCIS grade with the histological grade of the subsequent iIBC.
Patients and Methods:
In this population-based, retrospective cohort study, the Netherlands Cancer Registry collected information on 25,719 women with DCIS diagnosed in the period 1989–2021 who underwent BCS. Of these 19,034 (74%) received adjuvant radiotherapy. Kaplan-Meier and Cox multivariable regression analyses were performed.
Results:
1,135 patients experienced an iIBC. The 10-year cumulative iIBC incidence rates for patients diagnosed in the periods 1989–1998, 1999–2008 and 2009–2021 and undergoing BCS only were 12.6%, 9.0% and 5.0% (P < 0.001), respectively. For those undergoing BCS with RT these figures were 5.7%, 3.7%% and 2.2%, respectively (P < 0.001). The 10-year iCBC rates remained stable: 4.4%, 5.5% and 4.5%, respectively, for the periods 1989– 1998, 1999–2008 and 2009–2021 (P = 0.24).
In the multivariable analysis, no statistically significant association was found between the grade of DCIS and the risk of iIBC, neither for the patients undergoing BCS only, nor for those undergoing BCS with RT; the hazard ratio’s for iIBC for DCIS grade 3 versus DCIS grade 1 were 1.11 (95% CI 0.84–1.48, P = 0.47) and 1.04 (95% CI 0.80–1.37, P = 0.75) for the patients who underwent BCS and those undergoing BCS with RT, respectively.
Information on grade of DCIS and grade of the subsequent iIBC was available for 721 patients (63.5%). Of the 189 patients with DCIS grade 1, 23 (12%) developed grade 3 iIBC, compared to 62 (24%) of the 256 patients with DCIS grade 2 and 123 (45%) of the 275 patients with DCIS grade 3 (P < 0.001)
Conclusions:
Since 1989 the risk of iIBC has decreased substantially in patients with DCIS undergoing BCS. Patients currently treated with BCS without RT have a risk of iIBC that is similar to the risk of developing iCBC and patients with adjuvant RT have a risk of iIBC which is 50 percent lower than the risk of iCBC. These low risks of iIBC might have implications for the clinical follow-up of patients with DCIS, such as the frequency of control visits and mammography. Our findings that DCIS grade is not significantly associated with the risk of iIBC stresses the need to intensify research on the tumour biology of DCIS. First, to identify those lesions that have a high risk to become invasive and recur as poorly differentiated invasive breast cancer and second, to identify the ones that are most sensitive to RT.
No conflict of interest.European Journal of Cancer 200S1 (2024) 113617
An interview with Annemiek van Hemert MD PhD, Surgical Oncology Department, Antoni van Leeuwenhoek-Netherlands Cancer Institute (AVL-NKI), Amsterdam Netherlands
MILAN, Italy—Four out of five patients with extensive nodal spread of their breast cancer could be spared extensive axillary dissection, if a new method of marking lymph nodes is used. That’s according to the findings of a study from Amsterdam reported at the European Breast Cancer Conference held in Milan.
Annemiek van Hemert MD PhD, from the Surgical Oncology Department of the Antoni van Leeuwenhoek-Netherlands Cancer Institute (AVL-NKI) in Amsterdam, The Netherlands, reported her finding from a study using the MARI protocol (“Marking Axillary lymph nodes with Radioactive Iodine seeds”) that predicts cancer outcomes. The protocol was developed at the AVL Hospital in 2014 and is now being used in several Dutch hospitals.
After her talk at the Milan conference, van Dr. van Hemert talked with the Audio Journal of Oncology’s chief correspondent Peter Goodwin:
Annemiek van Hemert MD PhD (Interview) IN: (GOODWIN) “Annemiek, it’s lovely to have you here in the podcast studio ….OUT: …..breast cancer conference, I’m Peter Goodwin. 10:15 secs
EBCC ABSTRACT 14
“Omission of axillary lymph node dissection in cN2-3 breast cancer patients with an excellent response on primary systemic treatment is safe: 4-year oncologic outcome of the MARI protocol”
https://cm.eortc.org/cmPortal/Searchable/ebcc14/config/Normal/#!sessiondetails/0000107230_0
https://www.ejcancer.com/article/S0959-8049(24)00210-7/fulltext
Background: Axillary lymph node staging techniques (e.g., sentinel lymph node biopsy, MARI = Marking Axillary lymph nodes with Radioactive Iodine seeds, and TAD = targeted axillary dissection) after primary systemic therapy (PST) are associated with low false negative rates. This observation has stimulated the use of tailored axillary treatment, including the omission of axillary lymph node dissection (ALND). However, robust data on the oncologic outcomes following tailored axillary treatment after PST are lacking, especially in patients with extensive nodal disease. In this study, we present the axillary recurrence rate, disease free survival and overall survival of node positive breast cancer patients with >3 suspicious axillary lymph nodes treated according to the MARI-protocol.
Methods: This prospective registry study was conducted between 2014 and 2021. We enrolled patients with pathologically proven node positive breast cancer and >3 suspicious axillary lymph nodes who were treated according to the MARI protocol. Clinical nodal stage pre-PST was assessed by FDG-PET/CT. After PST, the MARI node was excised. Patients with a pathologic complete response (pCR) of the MARI node received radiation treatment. Patients with residual disease of the MARI node received ALND plus radiotherapy (RT). Primary endpoint was axillary recurrence rate (aRR). Secondary endpoints were invasive disease-free survival (DFS) and overall survival (OS). Survival estimates were calculated using the Kaplan-Meier method.
Results: Of 218 patients included, 86 (39%) patients had hormone receptor positive (HR+)/ human epidermal growth factor 2 negative (HER2-) breast cancer; 41 (19%) HR+/HER2+; 36 (17%) HR-/HER2+ and 55 (25%) had triple negative (TN) breast cancer. Median (IQR) age was 50 (42–57) years. FDG-PET/CT identified extra-axillary lymph nodes (periclavicular/ parasternal) in 39% (n = 85) of the patients. 47% of patients (103 of 218) had a pCR of the MARI node and were treated with RT alone, whereas 53% of patients (115 of 218) had residual disease of the MARI node and underwent ALND plus RT. Median (IQR) follow up was 44 (26–62) months. As shown in table 1, aRR was 2.9% (n= 3) in the MARI-pCR group treated with RT alone and 3.5% (n = 4) in MARI-non pCR group treated with ALND and RT. Invasive DFS and OS was worst in MARI-non pCR patients who underwent ALND plus RT.
Conclusion: Omission of axillary lymph node dissection after PST in selected node positive breast cancer patients with >3 suspicious lymph nodes using the MARI protocol is associated with an excellent oncologic outcome.
MORE:
Breast cancer patients can safely avoid extensive removal of lymph nodes if they respond well to primary systemic treatment
Milan, Italy: Patients with breast cancer that has started to spread to the lymph nodes in the armpit can safely avoid extensive removal of the lymph nodes if their treatment is tailored to their response to cancer-killing therapies such as chemotherapy before surgery.
In a presentation to the 14th European Breast Cancer Conference today (Friday) in Milan, Annemiek Van Hemert, a doctor and PhD student in the Surgical Oncology Department of Antoni van Leeuwenhoek-Netherlands Cancer Institute (AVL-NKI) in Amsterdam (The Netherlands), said: “If we are able to predict the response based on the removal of only one lymph node, it means we can safely avoid extensive removal of the lymph nodes if no living tumour cells are left. This will avoid serious complications, such as painful swelling in the arm, known as lymphoedema.
“However, although clinicians use a number of staging techniques to predict the response, until now robust data on cancer outcomes have been lacking, especially in patients whose cancer has spread to more than three lymph nodes.”
Dr Van Hemert and colleagues, led by Professor Marie-Jeanne Vrancken Peeters at the AVL-NKI, carried out a study involving 218 patients between 2014 and 2021 to investigate cancer outcomes of the MARI protocol (“Marking Axillary lymph nodes with Radioactive Iodine seeds”). The protocol was developed at the AVL Hospital in 2014 and is now being used in several Dutch hospitals. Today’s presentation gives outcomes after four years for the rate of cancer recurrence in the axillary nodes, patients’ overall survival and disease-free survival.
“We focused on patients with more extensive axillary lymph node disease: the patients where we know there were cancer cells in more than three nodes. We used FDG-PET/CT scans to assess the extent of cancer spread to the lymph nodes,” said Dr Van Hemert [1].
“We marked the largest axillary lymph node with a radioactive iodine seed. After this, patients underwent primary systemic treatment: either chemotherapy or targeted therapies that find and attack cancer cells. Then surgery was performed. During the surgery, we only removed the marked lymph node, the MARI node, and examined it for any remaining living tumour cells.
“Whenever the MARI node showed there were no residual tumour cells, in other words a pathological complete response (pCR) to the primary systemic treatment, then we did not remove any additional lymph nodes. Patients who had residual disease in the MARI node had further lymph nodes removed: known as an axillary lymph node dissection. All patients received radiation treatment.”
The MARI procedure had a false negative rate of 7% which means that it missed living cancer cells in 7% of cases. After an average of 44 months (with a range of 26-62 months), the rate of cancer recurrence in the axillary nodes was 2.9% in the 103 patients who received radiation alone with no further lymph node removal – 47% of the study’s 218 patients.
“In addition, survival rates after 44 months in these patients were excellent,” said Dr Van Hemert. “The overall survival rate was 95%, and 89% of patients survived without a recurrence of invasive disease. This means that we can safely omit the extensive removal of axillary lymph nodes in patients who achieve a pCR in the MARI node after primary systemic treatment.”
The axillary recurrence rate in the 115 patients (53%) who required further lymph node removal was 3.5%, with an overall survival rate of 90% and a disease-free survival rate of 82%.
She said primary systemic treatment had improved greatly in recent years, and up to 70% of patients treated this way achieved a pCR, but surgeons were still removing all the axillary lymph nodes. “The pathologist would say: ‘Nice, you have removed 18 lymph nodes and none of them contained residual tumour cells’. So this raised the question: did we do the right thing for the patient by removing so many nodes with all the ensuing complications?
“We hope that other clinicians will think of implementing this de-escalation strategy so that more patients with breast cancer will benefit from what we have shown: surgical removal of axillary nodes can be safely omitted in around 80% of patients treated with primary systemic therapy.”
The researchers will be collecting further data on outcomes over a longer period. They have also started the DESCARTES trial [2] to investigate the safety of omitting radiation treatment in a selected group of patients with tumours smaller than two centimetres in diameter, no evidence of the cancer spreading to the lymph nodes and pCR after primary systemic treatment.
The co-chair of the 14th European Breast Cancer Conference is Dr Fiorita Poulakaki, Head of the Breast surgery Department at Athens Medical Centre Hospital, Greece, and Vice President Europa Donna, the European Breast Cancer Coalition, and she was not involved with this particular research project. She commented: “When we treat patients for breast cancer, it is important to ensure that treatment itself causes as little harm to the patients as possible. The results from this study suggest a way to help us avoid side effects that affect the quality of life and can sometimes cause considerable long-term distress to patients. Every day we cure patients, making sure they live long lives, but at the same time we should care also about survivorship issues. We look forward to further results from this trial.”
An interview with:
Tim Rattay MBChB PhD, Consultant Breast Surgeon, University Hospitals of Leicester, Associate Professor in Breast Surgery, Leicester Cancer Research Centre, University of Leicester, England, UK. A report from the 14th European Breast Cancer Conference, Milan, Italy
MILAN, Italy—An artificial intelligence tool can predict the risk of lymphedema in a particular patient after breast cancer radiotherapy, according to research findings from Leicester University in the United Kingdom.
The 2024 European Breast Cancer Conference in Milan heard how AI can help cancer doctors to individualize radiotherapy regimens after surgery so as to minimize toxicity.
Tim Rattay MBChB PhD, Associate Professor in Breast Surgery at the Leicester Cancer Research Centre, University of Leicester and Consultant Breast Surgeon at the University Hospitals of Leicester in the UK, told the conference about his group’s machine-learning algorithm: PRE-ACT (Prediction of Radiotherapy side Effects using explainable AI for patient Communication and Treatment modification) that predicts post-operative lymphedema.
After reporting his research in Milan, he gave Peter Goodwin the details.
Tim Rattay MBChB PhD: IN: (GOODWIN) “Artificial intelligence …….OUT: ….. For the Audio Journal Oncology, I’m Peter Goodwin” 14:05 secs
EBCC Abstract no: 23:
“Development of an explainable AI prediction model for arm lymphoedema following breast cancer surgery and radiotherapy”,
https://cm.eortc.org/cmPortal/Searchable/ebcc14/config/Normal/#!sessiondetails/0000108900_0
MORE:
AI tool for breast cancer patients following surgery
An international team of researchers, led by the University of Leicester, has developed an artificial intelligence (AI) tool that can predict which breast cancer patients may be at risk of side effects after surgery and radiotherapy.
Dr Tim Rattay, a consultant breast surgeon and Associate Professor at the University’s Leicester Cancer Research Centre, presented the development at the 14th European Breast Cancer Conference (EBCC14) in Milan this week (21 March), explaining that the tool will be tested in a clinical trial towards the end of the year in the UK, France, and Netherlands.
Some of the factors that increase the risk of side effects are already known, but the PRE-ACT project (Prediction of Radiotherapy side Effects using explainable AI for patient Communication and Treatment modification) aims to make more accurate predictions for each individual patient, as well as providing easily understandable explanations for doctors and patients.
Dr Rattay said: “The explainable AI tool shows the reasoning behind its decision-making so it’s easier not only for doctors to make decisions, but also to provide data-backed explanations to their patients.
“Thankfully, long-term survival rates from breast cancer continue to increase, but for some patients, this means having to live with the side effects of their treatment, including skin changes, scarring, lymphoedema, which is a painful swelling of the arm, and even heart damage from radiation treatment.
“That’s why we’ve developed an AI tool to inform doctors and patients about the risk of chronic arm swelling after surgery and radiotherapy for breast cancer. We hope this will assist doctors and patients in choosing options for radiation treatment and reduce side effects for all patients.”
The team of researchers used information from European datasets (REQUITE, Hypo-G and CANTO) on 6,361 breast cancer patients to train different machine learning algorithms to predict arm swelling up to three years after surgery and radiotherapy.
The AI tool correctly predicted lymphoedema in an average of 81.6% of cases and correctly identified patients who would not develop it in an average of 72.9% of cases. The overall predictive accuracy of the model was 73.4%.
Dr Rattay said: “Patients identified at higher risk of arm swelling could be offered additional supportive measures, such as wearing an arm compression sleeve during treatment, which has been shown to reduce arm swelling in the long-term. Clinicians may also use this information to discuss options for lymph node irradiation in patients, where its benefit may be fairly borderline. We will test the effect of the prediction model on clinician and patient behaviour and use of the prophylactic arm sleeve in the proposed clinical trial.”
The researchers will incorporate the current AI model into software that can provide evaluations and predictions to doctors and patients. This will be tested when the PRE-ACT-clinical trial starts later this year. They are also developing the tool further so that it can predict other side effects, such as skin and heart damage.
Dr Guido Bologna, Associate Professor at the University of Applied Sciences and Arts of Western Switzerland in Geneva, and co-investigator on the project added: “The final, best-performing model makes predictions using 32 different patient and treatment features, including whether or not patients had chemotherapy, whether sentinel lymph node biopsy under the armpit was carried out, and the type of radiotherapy given.”
As part of the trial, the researchers will collect data on genetic markers and imaging data to improve the accuracy of the AI tools, although these will not be used to make predictions in the PRE-ACT trial.
The study is funded by the Horizon Europe programme and it is hoped that approximately 780 patients will take part in the clinical trial by early 2026, with a follow up period of two years.
An interview with Yasmin Civil MD PhD, UMC Hospital, Amsterdam, Netherlands.
MILAN, Italy—Offering MRI-guided partial breast irradiation before surgery to patients with low-risk breast cancer could become the norm, according to Yasmin Civil MD PhD from the UMC Hospital in Amsterdam, who reported five-year results from the ABLATIVE trial of pre-operative MRI-guided single dose partial breast irradiation to the 14th European Breast Cancer Conference.
Partial breast irradiation, given before breast-conserving surgery, achieved durable pathologic complete remissions in low-risk breast cancer, and even held out the prospect of surgery-free treatment for some patients.
After giving her talk in Milan, Dr. Civil discussed the details of the ABLATIVE study findings with Peter Goodwin:
AUDIO JOURNAL OF ONCOLOGY Podcast:
IN: (PETER GOODWIN) “If you are treating …… …OUT: …… for the Audio Journal of Oncology, I’m Peter Goodwin. (9:13sec)
ABSTRACT:
https://www.ejcancer.com/article/S0959-8049(24)00203-X/abstract#%20
https://www.audiomedica.com/wp-content/2025/09/250908-Yasmin-Civil-Pre-Operative-Partial-Breast-Irradiation-Marked-Benefit-in-Low-Risk-Breast-Cancer-AJO-PRODUCTION-MASTER-copy.mp3Yasmin Civil MD PhD“Pre-operative magnetic resonance guided single dose partial breast irradiation: five-year results of the ABLATIVE trial”
BACKGROUND:
Preoperative partial breast irradiation (PBI) can result in decreased irradiated volumes compared with postoperative PBI and may therefore lead to lesstoxicity and improved cosmetic outcome. In the multicenter ABLATIVE trial (NCT02316561), 15/36 patients achieved pathologic complete response 6–8 months after preoperative single-dose PBI. We now present long-term outcomes of preoperative single-dose PBI and breast conserving surgery (BCS) including late toxicity, tumor recurrence, survival, cosmetic outcome and quality of life in low-risk breast cancer patients.
PROTOCOL:
The ABLATIVE-2 trial is a multicenter prospective single-arm trial using single-dose ablative PBI in low-risk breast cancer patients. Patients ≥ 50 years with non-lobular invasive breast cancer ≤ 2 cm, grade 1 or 2, estrogen receptor-positive, HER2-negative, and tumor-negative sentinel node procedure are eligible. PBI treatment planning performed using a radiotherapy planning CT and -MRI in treatment position. The treatment delivery on a conventional or MR-guided linear accelerator. The prescribed radiotherapy dose is a single dose of 20 Gy to the tumor, and 15 Gy to the 2 cm of breast tissue surrounding the tumor. Follow-up MRIs, scheduled at baseline, 2 weeks, 3, 6, 9, and 12 months after PBI, are combined with liquid biopsies to identify biomarkers for pCR prediction. BCS performed 12 months after radiotherapy or after 6 months, if MRI does not show a radiologic complete response. The primary endpoint is the pCR rate after PBI. Secondary endpoints are radiologic response, toxicity, quality of life, cosmetic outcome, patient distress, oncological outcomes, and the evaluation of biomarkers in liquid biopsies and tumor tissue.
An interview with Heather McArthur MD MPH, Clinical Director of Breast Cancer, Komen Distinguished Chair in Clinical Breast Research, University of Texas Southwestern Medical Center, Dallas, USA
MILAN, Italy—Patients with early breast cancer testing positive for estrogen receptor (ER+) and negative for human epidermal growth factor receptor 2 (HER2-) had markedly better outcomes when immune checkpoint inhibitor therapy was added to their standard chemo- and endocrine therapies before and after surgery.
The KEYNOTE-756 phase 3 clinical trial found that patients benefited from having neo-adjuvant and adjuvant pembrolizumab regardless of their age or menopausal status.
The study was reported at the 14th European Breast Cancer Conference by Heather McArthur MD MPH, Clinical Director of the Breast Cancer Program and Komen Distinguished Chair in Clinical Breast Research, University of Texas Southwestern Medical Center in Dallas, USA, co-author of the study, led by Javier Cortés MD, Director of the International Breast Cancer Centre in Barcelona, Spain.
After her talk she met up with Audio Journal of Oncology reorter Peter Goodwin.
AJO podcast interview with Heather McArthur:
IN: “Hello and welcome to the Audio Journal of Oncology…
OUT: ….For the Audio Journal of Oncology, I’m Peter Goodwin.
NOTES:
The international KEYNOTE-756 trial (which has been running for eight years) randomized 1278 patients with ER-positive, HER2 negative, invasive ductal carcinoma to receive pembrolizumab or placebo in addition to neoadjuvant chemotherapy followed by adjuvant pembrolizumab or placebo in combination with an endocrine therapy.
First author Javier Cortés MD, Director of the International Breast Cancer Centre in Barcelona, Spain, said the pathological complete response rate (PCR) was 24.3% in patients treated with pembrolizumab compared to 15.6% in patients treated with the placebo.
Speaking before the EBCC 14 conference, Dr. Fatima Cardoso, Director of the Breast Unit of the Champalimaud Clinical Centre in Lisbon, Portugal (the principal investigator for the trial) said that Keynote 756 showed the addition of pembrolizumab to neoadjuvant chemotherapy significantly increased pathological response at the time of surgery, and that this had been true regardless of PD-L1 levels and oestrogen receptor positivity. However, the study found a bigger benefit with higher PD-L1 levels and in ER-low tumors.
ABSTRACT:
14th European Breast Cancer Conference Abstract no: 4:
“Neoadjuvant pembrolizumab or placebo + chemotherapy, followed by adjuvant pembrolizumab or placebo plus endocrine therapy for early-stage high-risk ER+/HER2− breast cancer: Results from the phase 3 KEYNOTE-756 study”
https://www.ejcancer.com/article/S0959-8049(24)00200-4/fulltext
An interview with:
Laura J. van ’t Veer PhD, Professor of Laboratory Medicine, Co-leader of the Breast Oncology Program, Director of Applied Genomics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.
MILAN, Italy—Around 25 per cent of patients with newly-diagnosed triple negative breast cancer will not benefit from neoadjuvant checkpoint inhibitor immunotherapy with pembrolizumab—even though it improves outcomes among the remaining majority. This finding comes from the I-SPY2 TRIAL and was reported at the 2024 European Breast Cancer Conference, held in Milan, Italy, by Laura van ’t Veer, Leader of the Breast Oncology Program at the University of California in San Francisco.
A subset of patients with triple-negative early-stage breast cancers, identified in the study through a gene test as having “response predictive sub-types” had a very low likelihood of response to neoadjuvant pembrolizumab, suggesting that such patients could be spared the potential toxicities of immunotherapy.
After her talk in Italy Dr van ’t Veer met up with Audio Journal of Oncology reporter Peter Goodwin to discuss the I-SPY findings.
INTERVIEW: Laura J. van ’t Veer PhD
“Hello, Peter Goodwin her with the Audio Journal of Oncology………..New drugs for breast cancer are traditionally tested in triple negative ……….. from me, Peter Goodwin, Good-bye” 15:46 secs
EBCC 2024 ABSTRACT 2LBA
“Immune subtyping in the Response Predictive Subtypes (RPS) identifies a subset of triple negative (TN) early- stage breast cancer patients with a very low likelihood of response to neoadjuvant immunotherapy (IO): results from 5 IO arms of the I-SPY2 TRIAL”
https://cm.eortc.org/cmPortal/Searchable/ebcc14/config/Normal/#!sessiondetails/0000107210_0
Abstract title:
Immune subtyping in the Response Predictive Subtypes (RPS) identifies a subset of triple negative (TN) early-stage breast cancer patients with a very low likelihood of response to neoadjuvant immunotherapy (IO): results from 5 IO arms of the I-SPY2 TRIAL
Authors:
D.M. Wolf1,, C. Yau2,, J. Haan3,, D. Wehkamp3,, A. Witteveen3,, A. Glas3,, M. Campbell2,, R. Nanda4,, J. Chien5,, R. Shatsky6,, C. Isaacs7,, A. Barcura3,, L. Mittempergher3,, M. Kuilman3,, D. Yee8,, A. DeMichele9,, J. Perlmutter10,, L. Pusztai11,, L. Esserman2,, L.J. van ‘t Veer PhD12,.1University California San Francisco, Laboratory Medicine, San Francisco, USA.2University California San Francisco, Surgery, San Francisco, USA.3Agendia, Research and Development, Amsterdam, The Netherlands.4University Chicago, Medicine, Chicago, USA.5University California San Francisco, Medicine, San Francisco, USA.6University California San Diego, Medicine, San Diego, USA.7Georgetown University, Medicine, Washington DC, USA.8University Minnesota, Masonic Cancer Center, Minneapolis, USA.9University Pennsylvania, Medicine, Philadelphia, USA.10Gemini Group, Advocacy, Ann Arbor, USA.11Yale University, Medicine, New Haven, USA.12University California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, USA.
Background:
Neoadjuvant immunotherapy (IO) has become standard of care for early stage TN breast cancer. However, not all patients respond and IO poses significant risk of permanent, life altering immune related adverse events (iRAEs) including adrenal insufficiency and thyroid dysfunction. Previously we showed immune gene expression signatures dominated by STAT1/chemokine/cytokine/dendritic markers associate with pathologic complete response (pCR) in TN treated with IO and developed a clinically applicable Immune classifier (ImPrint) predicting response to IO for both TN and HR+ that is now being used in I-SPY2.2 as part of the Response Predictive Subtypes. This initial ImPrint classifier performed with high accuracy for TN and HR+ patients combined, though we noticed that this classifier could be further improved by reducing the false-negative rate for TN (ie high negative predictive value). Here we report the performance of a refined version of ImPrint for TN patients (ImPrintTN) from 5 IO arms of the I-SPY2 trial.
Methods:
150 TN patients from 5 pooled IO arms (anti-PD1, anti-PDL1/PARPi, anti-PD1/TLR9 dual-IO, and anti-PD1 +/- LAG3 dual-IO, all plus taxane/anthracycline) and 128 patients from the taxane/anthracycline concurrent control arm were included in this analysis. Patients in IO arms with FFPE pre-treatment biopsies were divided into treatment- and response-balanced training and test sets; and an IO-response classifier was developed including additional immune signaling and checkpoint markers using pre-treatment mRNA from the training set (n=55). Patient biopsies were classified ImPrintTN+ (likely sensitive) vs. ImPrintTN- (likely resistant), by Agendia Inc using pre-treatment expression data. Performance of ImPrintTN for predicting pCR to IO in the test set, and overall was characterized using standard methods.
Results:
Overall, the pCR rate for TN over the 5 pooled IO arms was 54%. 66% of TN patients were ImPrintTN+. pCR rates with IO in the independent test set were 71% in ImPrintTN+ vs. 22% in ImPrintTN- (delta-pCR rate 49%; sensitivity=87%; negative predictive value (NPV)=78%). Similar results were observed in all 5IO arms taken together (test plus training), where pCR rates with IO were 74% in ImPrintTN+ vs. 16% in ImPrintTN- (delta-pCR rate 58%; sensitivity=90%; NPV=84%). In the control arm, pCR rates were 30% in ImPrint+ and 15% in ImPrint-, delta-pCR 15%).
Conclusions:
The https://www.audiomedica.com/wp-content/2025/08/240320-Laura-van-t-Veer-EBCC-2024-Predictive-Subtypes-AJO-PRODUCTION-MASTER-.mp3
Laura J. van ‘t Veer, PhDfor TN predicts response and non-response to a variety of IO regimens tested in I-SPY2. Within the ImPrintTN- subset, pCR rates to IO regimens are very low, and similar to that of non-IO containing regimens. Prospective validation is ongoing in I-SPY2.2. Our current data suggest that ImPrintTN may help inform prioritization of IO vs other treatments for TN patients to best balance likely benefit vs risk of serious irAEs.
Érica A. Oliveira PhD: How to Overcome Drug Resistance: Patient Derived Organoids Study Finds Epigenetic Pathways in Colorectal Cancer
Interviews with:
Érica A. Oliveira PhD, Senior Scientific Officer, Genomics and Evolutionary Dynamics, Institute of Cancer Research, Sutton, London UK
And:
Christopher Sng MD, Clinical Research Fellow, Institute of Cancer Research and Royal Marsden Hospital, London
LONDON, UK—New insights into understanding and overcoming cancer drug resistance have been announced by researchers from the Institute of Cancer Research and the Royal Marsden Hospital in London.
Érica Oliviera PhD, Senior Scientific Officer for Genomics and Evolutionary Dynamics, and Christopher Sng MD, Clinical Research Fellow, both at the Institute of Cancer Research and Royal Marsden Hospital in London, tell the Audio Journal of Oncology’s Peter Goodwin about their research on colorectal cancer using so-called “organoids” which perform like miniature replicas of human organs.
The research shows how epigenetic factors control drug resistance by influencing DNA expression. The findings set the scene for combatting resistance by using, agents, protocols and combinations designed to modify these epigenetic pathways.
The research is published in Cancer Research Volume 85 Issue 15, 1st August 2025:
“Epigenetic Heritability of Cell Plasticity Drives Cancer Drug Resistance through a One-to-Many Genotype-to-Phenotype Paradigm”
[Cancer Res (2025) 85 (15): 2921–2938]
https://aacrjournals.org/cancerres/article/85/15/2921/763888/Epigenetic-Heritability-of-Cell-Plasticity-Drives
https://www.audiomedica.com/wp-content/2025/08/Erica-Oliveira-PRODUCTION-MASTER.mp3Erica Oliveira PhDABSTRACT
Cancer drug resistance is multifactorial, driven by heritable (epi)genetic changes but also by phenotypic plasticity. In this study, we dissected the drivers of resistance by perturbing organoids derived from patients with colorectal cancer longitudinally with drugs in sequence. Combined longitudinal lineage tracking, single-cell multiomics analysis, evolutionary modeling, and machine learning revealed that different targeted drugs select for distinct subclones, supporting rationally designed drug sequences. The cellular memory of drug resistance was encoded as a heritable epigenetic configuration from which multiple transcriptional programs could run, supporting a one-to-many (epi)genotype-to-phenotype map that explains how clonal expansions and plasticity manifest together. This epigenetic landscape may ensure drug-resistant subclones can exhibit distinct phenotypes in changing environments while still preserving the cellular memory encoding for their selective advantage. Chemotherapy resistance was instead entirely driven by transient phenotypic plasticity rather than stable clonal selection. Inducing further chromosomal instability before drug application changed clonal evolution but not convergent transcriptional programs. Collectively, these data show how genetic and epigenetic alterations are selected to engender a “permissive epigenome” that enables phenotypic plasticity.
Significance:
Drug resistance is driven by genetic–epigenetic memory that enables cancer cells to adopt multiple phenotypic states depending on environmental conditions, supporting integration of evolutionary principles into biomarker discovery and personalized treatment strategies.
Audio Journal of Oncology, August 5th, 2025
An interview with:
Christian Singer MD,
Head, Center for Breast Health, Department of Obstetrics & Gynecology, Comprehensive Cancer Center, Medical University of Vienna.
CHICAGO, USA—Your patients whose triple-negative breast cancers test positive for BRCA 1/2 mutations, could do better if you gave them the poly ADP ribose polymerase (PARP) inhibitor olaparib together with carboplatin, as neoadjuvant therapy, rather than a standard docetaxel/epirubicin/cyclophosphamide combination.
That’s according to the prospective randomized phase two ABCSG 45 trial reported by Austrian researchers at the 2025 Annual Meeting of the American Society of Clinical Oncology held in Chicago. Peter Goodwin heard the details from first author Christian Singer of the University of Vienna:
Audio Journal of Oncology: Christian Singer, Medical University of Vienna.
ASCO 2025 ABSTRACT 510:
Title:
Prospective randomized phase II trial to assess the efficacy and safety of neo-adjuvant olaparib/carboplatin (OC) in comparison to docetaxel/epirubicin/cyclophosphamide (TAC) in patients with early triple-negative breast cancer (TNBC) with homologous recombination deficiency (HRD): Primary results from the ABCSG 45 trial.
Background:
Carboplatin-based regimen are effective in patients (pts) with eTNBC, and olaparib improves the outcome of pts with BRCA1/2 pathogenic variants (PV), but the safety / efficacy of OC co-treatment in HRD-positive TNBC is unknown. ABCSG 45 (EU CT 2024-512821-10) is a prospective multicenter phase II study investigating the efficacy and tolerability of OC compared to conventional chemotherapy in HRD-positive eTNBC.
Methods:
Pts with HRD (Myriad genetics)-positive eTNBC were randomized to 6 cycles of olaparib (100 mg bid, days 4-16) / carboplatin (AUC 5) q3w, or 6 cycles of docetaxel/epirubicin/cyclophosphamide (75/50/500) q3w (TAC). In an initial dose-finding phase, 100 mg bid was identified as olaparib combination dose. Stratification factors were tumoral BRCA1/2 and menopausal status. Primary endpoint was centrally assessed residual cancer burden (RCB), pCR and QoL were secondary endpoints. Planned sample size was 90 pts, randomized 1:1 to achieve 80% power (two-sided alpha=0.05) to detect a RCB 0/I difference of 31%. Differences between treatment arms were assessed with a two-sided Cochran Mantel-Haenszel test using stratification factors. Pre-defined subgroup analysis was performed with logistic regression.
Results:
A total of 90 pts (OC: n=46; TAC: n=44), of whom 42 (47%) were BRCA1/2 PV carriers, were randomized between November 2019 and December 2023. Median age was 50.5 years (range 27.0-80.0). 40% had cT1, 55.6% cT2, and 4.4% cT3/4 tumors, and 60% of pts were clinically N0. 94.4% of tumors were G3, and Ki67 was >60% in 71.1%. Overall, the RCB0/I rate with OC was 52.2% vs. 70.5% with TAC (stratified risk difference = -18.8% (95%CI: -39.6% to 2.0%); p=0.068). In pts with BRCA1/2 PV, RCB0/I rates were comparable: 77.3% (OC) vs. 65.0% (TAC), while in 47 pts with BRCA1/2 wild type (WT), OC was significantly less effective: RCB0/I of 29.2% vs 73.9% in TAC (interaction p=0.008). pCR was achieved in 47.8% (OC) vs 59.1% (TAC; p=0.231). In pts with a BRCA1/2 PV, OC resulted in 77.3% pCR rate, vs. TAC 65.0%, in BRCA1/2 WT pts pCR was achieved by 20.8% (OC) vs. 56.5% (TAC) (interaction p=0.021). OC treatment resulted in more ≥ grade 3 hematologic toxicities with 30% vs 3% thrombocytopenia and 43% vs 18% neutropenia but caused fewer non-hematological toxicities.
Conclusions:
In this prospective randomized study in HRD-positive TNBC, 6 cycles of TAC resulted in strikingly high RCB0/I and pCR rates, independent of BRCA1/2 status. 6 cycles of OC achieved a pCR rate of >77% in BRCA1/2 PV but were less effective in pts with BRCA1/2 WT disease. These results may help to optimize neoadjuvant treatment strategies in TNBC.
This research was conducted with support from AstraZeneca Austria GmbH
Authors:
Christian Singer, Dominik Hlauschek, Daniel Egle, Zsuzsanna Bago-Horvath, Georg Pfeiler, Christine Brunner, Christian Peters-Engl, Edgar Petru, Daniel Reimer, Renate Pusch, Michael Seifert, Petra Pichler, Christoph Suppan, Annette Reiner, Richard Greil, Yen Tan, Rupert Bartsch, Katharina Knoll, Anna Kermanidis, Michael Gnant
Organizations
Department of Obstetrics and Gynecology and Center for Breast Health, Comprehensive Cancer Center, Medical University of Vienna and Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria, Austrian Breast and Colorectal Cancer Study Group, Wien, Austria, Department of Gynecology, Breast Cancer Center Tirol, Medical University of Innsbruck and Austrian Breast and Colorectal Cancer Study Group, Innsbruck, Austria, Department of Pathology and Comprehensive Cancer Center, Medical University of Vienna, and Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria, Department of Gynecology, Breast Cancer Center Tirol, Medical University of Innsbruck, Innsbruck, Austria, Institute for Gynecological Oncology and Senology, Karl Landsteiner Society, Hietzing Hospital, Vienna, Austria, Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria, Ordensklinikum Linz, Barmherzige Schwestern, Abteilung Interne I, Medizinische Onkologie und Hämatologie, Linz, Austria, Clinical Department for Internal Medicine 1, University Hospital St Poelten, Karl Landsteiner University of Health Sciences, St. Poelten, Austria, Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria, Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria, IIIrd Medical Department, Paracelsus Medical University, Salzburg Cancer Research Institute-Center for Clinical Cancer and Immunology Trials, Cancer Cluster Salzburg, and Austrian Breast and Colorectcal Cancer Study Group, Salzburg, Austria, Department of Obstetrics and Gynecology and Center for Breast Health, Comprehensive Cancer Center, Medical University of Vienna, Wien, Austria, Department of Medicine I, Division of Oncology, Medical University of Vienna and Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria, Austrian Breast and Colorectal Cancer Study Group, Viena, Austria, Comprehensive Cancer Center, Medical University of Vienna and Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria
https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.510
With:
Sara M Tolaney MD MPH, Chief, Division of Breast Oncology, Dana-Farber Cancer Institute, Associate Professor of Medicine, Harvard Medical School, Boston USA
And interviews with:
Rebecca Dent MD,
Deputy Chief Executive Officer, National Cancer Center, Singapore
And:
Giuseppe Curigliano MD PhD,
Director, Early Drug Development for Innovative Therapies Division, European Institute of Oncology, University of Milan, Milan, Italy
CHICAGO, USA—Patients with HER2 positive advanced or metastatic breast cancer lived significantly longer without having any return of their disease after treatment with a combination including the antibody drug conjugate trastuzumab deruxtecan (T-DXd) in comparison with similar patients treated with the current standard of care: a taxane plus trastuzumab and pertuzumab.
This was revealed in interim finding from the the DESTINY-Breast09 study reported at the 2025 Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago by Sara M Tolaney MD MPH of the Dana-Farber Cancer Institute in Boston USA.
To comment on the DESTINY findings Peter Goodwin interviewed Rebecca Dent, from the National Cancer Center, in Singapore. Giuseppe Curigliano MD PhD of the University of Milan explained how T-DXd had already contributed to the emerging landscape of antibody drug conjugate therapies for breast cancer.
ASCO ABSTRACT TITLE:
Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (a/mBC): Interim results from DESTINY-Breast09.
Background:
DESTINY-Breast09 (NCT04784715) is a global, randomized Phase 3 study assessing the efficacy and safety of 1L T-DXd ± P vs THP in 1157 pts with HER2+ a/mBC. The CLEOPATRA study established THP as standard of care in this setting over a decade ago.
Methods:
Eligible pts had centrally confirmed HER2+ (IHC 3+ or ISH+) a/mBC and no prior chemotherapy or HER2-directed therapy for a/mBC ([neo]adjuvant HER2-directed therapy / chemotherapy with a disease-free interval of >6 months [mo] and ≤1 line of endocrine therapy for metastatic disease permitted). Pts were randomized 1:1:1 to T-DXd 5.4 mg/kg (+ placebo), T-DXd + P, or THP, stratified by de-novo vs recurrent disease, and hormone receptor (HR) and PIK3CA mutation status. In this planned interim analysis, data for T-DXd + P vs THP are presented; the T-DXd + placebo arm remains blinded until final PFS analysis. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) in the intent-to-treat population. Other endpoints included overall survival (OS), PFS by investigator (INV), objective response rate (ORR), duration of response (DOR), and safety.
Results:
Among the pts randomized to T-DXd + P (n=383) and THP (n=387), 52% had de-novo disease and 54% had HR+ status; demographic and disease characteristics were well balanced. At this interim data cutoff (Feb 26, 2025; median follow up 29 mo; 38% mature for PFS), T-DXd + P significantly improved PFS by BICR (hazard ratio 0.56; 95% CI 0.44, 0.71; P<0.00001) and INV (Table). PFS benefit was consistent across all subgroups. OS data were immature. Median response duration with T-DXd + P exceeded 3 years (Table). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 63.5% and 62.3%, and serious TEAEs in 27.0% and 25.1%, of pts in the T-DXd + P and THP groups, respectively. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 46 (12.1%; predominantly Gr 1/2; n=2 [0.5%] Gr 5) pts who received T-DXd + P, and 4 (1.0%; all Gr 1/2) who received THP.
Conclusions:
T-DXd + P demonstrated a statistically significant and clinically meaningful improvement in PFS vs THP that was consistently observed across all subgroups and may represent a new 1L standard of care in HER2+ a/mBC; no new safety signals were identified.
Interview with Erica L. Mayer MD MPH, Director of Breast Cancer Clinical Research, Breast Oncology Program, Dana-Farber Cancer Institute, Boston, USA.
With comment from:
Pat Price MD, Imperial College London, UK, Chair, Global Coalition for Radiotherapy.
CHICAGO, USA—Avoiding therapy discontinuation was the focus of the TRADE study looking at abemaciclib dose escalation among patients with early-stage hormone-receptor positive HER2 negative breast cancer.
At the 2025 Annual Meeting of the American Society of Clinical Oncology Erica L. Mayer MD MPH, Director of Breast Cancer Clinical Research at the Dana-Farber Cancer Institute in Boston, USA, reported that by starting patients on a low dose of abemaciclib, and then escalating to the target dose, significantly more of them reached the therapeutic dose without the risk of discontinuation.
PODCAST:
(SARAH MAXWELL): “In patients with early breast cancer, starting with a low dose of the CDK 4/6 inhibitor abemaciclib, then escalating to the therapeutic dose, has significantly reduced non-compliance and improved outcomes.
I’m Sarah Maxwell. Hello, and welcome to the Audio Journal of Oncology, reporting from the 2025 Annual Meeting of ASCO: the American Society of Clinical Oncology, held in Chicago.
The TRADE study looked at dose escalation in patients with hormone receptor positive, HER2 negative breast cancer, and lead author Erica Mayer, from the Dana-Farber Cancer Institute in Boston, has been talking with our reporter Peter Goodwin:”
INTERVIEW: Erica L. Mayer MD MPH, Boston, USA.
COMMENT: Pat Price MD, Imperial College London, UK.
(SARAH MAXWELL) “Peter was talking with Professor Pat Price, from Imperial College in London, UK, who chairs the Global Coalition for Radiotherapy; and before her: with Erica Mayer Director of Breast Cancer Clinical Research, at the Dana-Farber Cancer Institute in Boston, USA.
You’ve been listening to the Audio Journal of Oncology. That’s all for now. More news from the world of cancer medicine very soon. From me, Sarah Maxwell, good-bye.
ASCO 2025 Abstract 517
The TRADE study: A phase 2 trial to assess the tolerability of abemaciclib dose escalation in early-stage HR+/HER2- breast cancer.
https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.517
Background:
The CDK4/6 inhibitor abemaciclib (abema) is approved with adjuvant endocrine therapy (ET) for high-risk node positive hormone receptor positive (HR+) HER2- breast cancer. This regimen reduces cancer recurrence, yet therapy may be complicated by toxicity, limiting patient (pts) ability to maintain dose or continue medication. In the phase III monarchE study, 25.8% of pts discontinued abema early for reasons other than recurrence, 18.5% for adverse events (AEs), and 43.6% required dose reduction. Experiences with other targeted therapies suggest initial dose escalation may reduce toxicity and discontinuation. TRADE is a prospective, single-arm, phase 2 study evaluating whether a dose-escalation strategy of adjuvant abema improves drug tolerability.
Methods:
Eligible pts had node-positive HR+/HER2- breast cancer and were candidates for adjuvant abema with ET. All pts started abema at 50 mg BID for 2 weeks (wks), escalated to 100 mg BID for 2 wks, then escalated to final dose of 150 mg BID onwards. Escalation required absence of ongoing grade 3/4 or persistent grade 2 toxicity; anti-diarrheal medication was used as needed.
The primary endpoint, measured at 12 wks, was a composite rate of discontinuation of abema for any reason or inability to reach or maintain the 150 mg dose. Based on assumptions from monarchE, the experimental hypothesis was that a dose-escalation schedule of abema would significantly reduce rate of the composite primary endpoint at 12 wks from 40%.
Results:
90 pts enrolled, 89 evaluable for the primary endpoint (1 progression before 12 wks). Median age was 58 [range 24-78], 4% were Black, 3% were Hispanic. 48% had stage II disease, 52% had stage III, all received AI, 14% concurrent OFS. The study achieved the predefined primary endpoint with 26 pts (29.2%; 90% CI [21.3-38.2]; p=0.046) meeting the composite endpoint at 12 wks: 6 (6.7%) for early discontinuation (3 [3.4%] for toxicity), 8 (9.0%) for inability to reach 150 mg, and 12 (13.5%) for dose reduction from 150 mg. The most frequent >grade 2 treatment related AEs by 12 wks were neutropenia (23.3%), diarrhea (22.2%), and fatigue (20%). Rates of clinically significant diarrhea (> grade 2) within 0-4, 4-8, and 8-12 wks were 5.6%, 14.6%, 15.3%, in contrast to rates from monarchE of 20.5%, 12.1%, 7.3% in the same periods.
Conclusions:
The TRADE study is a positive trial meeting its primary endpoint. Use of an adjuvant abema dose escalation strategy allowed a greater number of pts (70.8%) to reach and maintain the 150 mg dose at 12 wks than in monarchE. Early discontinuation was infrequent, and 93.3% were continuing therapy at 12 wks. Reduced incidence and severity of clinically important toxicity such as diarrhea was observed. This dosing strategy could be considered when initiating adjuvant abemaciclib. Further follow-up will assess long-term tolerability, dosing maintenance beyond 12 wks, and correlative analyses. Clinical trial information: NCT06001762.
An interview with:
David R Spigel FASCO, MD, Chief Scientific Officer, Sarah Cannon Research Institute, Nashville, Tennessee, US
With comment from:
Luis G Paz-Ares MD PhD
Chair of Medical Oncology, Hospital Universitario 12 de Octubre, Universitario de Madrid
CHICAGO, USA—Although patients with early non-squamous non-small cell lung cancer can be cured by surgery alone, many are not. So, researchers in Nashville USA set up an international, multi-center, prospective randomized a study to examine whether a gene molecular assay could help by identifying patients at higher risk and treating them with adjuvant chemotherapy. Improved outcomes were reported at the 2025 Annual Meeting of the American Society of Clinical Oncology.
After his ASCO talk the study leader, David Spigel MD, Chief Scientific Officer at the Sarah Cannon Research institute in Nashville, gave the details to Audio Journal Oncology reporter Peter Goodwin.
ASCO 2025 Abstract LBA8027:
“An international, multicenter, prospective randomized trial of adjuvant chemotherapy for stage Ia-IIa non-small cell lung cancer identified as high-risk by a 14-gene molecular assay.”
https://ascopubs.org/doi/10.1200/JCO.2025.43.17_suppl.LBA8027
Abstract
LBA8027
Background: Despite advances in late-stage treatments, survival of early-stage non-small cell lung cancer (NSCLC) remains dismal, with 5-year disease free survival (DFS) of only 65% even in stage Ia. Preliminary, non-randomized clinical data suggest the predictive efficacy of RiskReveal, a 14-gene expression profile, in identifying stage Ia-IIa patients with non-squamous NSCLC who benefit from adjuvant therapy. We undertook an international, multicenter, randomized clinical trial to confirm these findings. Here, we report the results of an early interim analysis that was planned to detect a large discrepancy in outcomes between arms.
Methods: 421 patients who underwent resection of stage pIa-IIa NSCLC were categorized as low-, intermediate-, or high-risk by the RiskReveal assay. Intermediate- and high-risk patients were randomized to observation or to 4 cycles of platinum-based adjuvant chemotherapy. The modified intent-to-treat (mITT) population was defined as randomized patients who continued to meet eligibility criteria either at the time of chemotherapy initiation or at randomization to observation. The primary endpoint was DFS in the mITT population, defined as the time from randomization to disease recurrence, exclusive of new primary lung cancer, or death from any cause. DFS was compared between arms using a log-rank test and Kaplan-Meier analysis. An early interim analysis was planned with a type I error rate of 0.02.
Results: Of 194 evaluable patients at the time of the interim analysis, 87 had been randomized to adjuvant chemotherapy (55% stage Ia), and 107 to observation (55% stage Ia). There were no significant differences between the groups with respect to age, sex, or tumor size >4 cm; median follow-up was 19.5 months in the chemotherapy arm and 19.0 months in the observation arm. At 24 months, adjuvant chemotherapy significantly improved DFS compared to observation, with a HR of 0.22 (95% CI 0.06, 0.76; p=0.0087). DFS at 24 months was 96% with adjuvant chemotherapy (95% CI 0.92, 1.00) vs. 79% with observation (95% CI 0.70, 0.90). Median DFS was not reached in either group.
Conclusion: A 14-gene molecular assay identified a high-risk population of stage Ia-IIa non-squamous NSCLC patients who benefited substantially from adjuvant chemotherapy. Improved survival in lung cancer is best achieved by optimizing outcomes in the earliest stages of disease. Identification of patients who benefit from adjuvant chemotherapy using this predictive test could result in a dramatic improvement in survival for the growing percentage of patients diagnosed in stages I-IIa. Although the study DSMB recommended a halt to enrollment, follow up continues and may provide further confirmation of this benefit. Clinical trial information: NCT01817192.
An interview with Jean Bourhis MD PhD, Head of Service of radiation oncology, Lausanne University Hospital, Lausanne, Switzerland.
And with:
Pat Price MD, Imperial College London, UK, Chair, Global Coalition for Radiotherapy.
SARAH MAXWELL
Disease free survival was extended in patients with head and neck cancers who had Nivolumab added to their standard post-operative therapy. I’m Sarah Maxwell. Welcome to this edition of the Audio Journal of Oncology.
Patients with high-risk cancers of the head and neck, had significant improvements in disease-free survival when treatment with the checkpoint inhibitor, nivolumab, was added to their standard chemo-radiotherapy after surgery. This finding was reported at the 2025 Annual Meeting of the American Society of Clinical Oncology, held in Chicago.
Radiation oncologist, Jean Bourhis, who is Head of the Radiation Oncology Service at Lausanne University Hospital, in Switzerland, has been telling Peter Goodwin more about his results from the NIVOPOSTOP phase III, randomized trial of adjuvant nivolumab:
INTERVIEW with:
Jean Bourhis MD PhD, Lausanne University Hospital, Switzerland
To get a comment on what Jean Bourhis had to say, Peter also met up with radiation oncologist, Pat Price, from Imperial College in London, UK, chair of the Global Coalition for Radiotherapy.
INTERVIEW with:
Pat Price MD, Imperial College London, UK, Chair, Global Coalition for Radiotherapy.
Pat Price was talking with Peter Goodwin for the Audio Journal of Oncology. That’s all for now. We’ll be back with more news for cancer doctors very soon. So, join us again wherever you listen to your podcasts. From me, Sarah Maxwell, good-bye!
ASCO 2025 Abstract LBA2:
“NIVOPOSTOP (GORTEC 2018-01): A phase III randomized trial of adjuvant nivolumab added to radio-chemotherapy in patients with resected head and neck squamous cell carcinoma at high risk of relapse.”
Conclusions (From ASCO 2025 Abstract):
“Adjuvant nivolumab added to chemoradiotherapy after surgery provided a statistically and clinically meaningful disease-free survival improvement in PD-L1 all-comers patients. This is the first time in over two decades that a therapy demonstrated superiority over standard of care in patients with resected locally advanced squamous cell cancer of the head and neck at high risk of relapse.”
Audio Journal of Oncology
An interview with:
Luis G Paz-Ares MD PhD, Chair of Medical Oncology, Hospital Universitario 12 de Octubre, Universitario de Madrid
Comment by:
Julie R. Gralow MD FACP FASCO, Chief Medical Officer and Executive Vice President, American Society of Clinical Oncology.
https://www.audiomedica.com/wp-content/2025/06/Luis-Paz-Ares-PRODUCTION-MASTER-.mp3CHICAGO, USA—Patients with extensive stage small cell lung cancer had longer disease-free survival and lived longer when the drug lurbinectedin (a DNA damaging agent) was added to their maintenance therapy after induction using standard immunochemotherapy. At the 2025 Annual Meeting of the American Society of Clinical Oncology (ASCO) the Audio Journal of Oncology heard from lead-author of the phase three IMforte study, Luis G Paz-Ares MD PhD from the University Hospital of the 12th of October in Madrid Spain and from Julie R. Gralow MD FACP FASCO, Chief Medical Officer and Executive Vice President of ASCO.
Podcast Script:
SARAH MAXWELL:
Hello and welcome to the Audio Journal of Oncology. I’m Sarah Maxwell. We’re reporting from the 2025 Annual Meeting of the American Society of Clinical Oncology held in Chicago.
There was encouraging news from the phase-three IMforte trial in patients with small cell lung cancer. The addition of a new DNA damaging agent – lurbinectedin – seems to be adding statistically significant and clinically meaningful extensions of progression-free and overall survival.
First Author Luis Paz-Ares, who chairs the Medical Oncology Department at the University of the 12th of October in Madrid, has been telling Peter Goodwin about the study findings:
INTERVIEW: Paz Ares/Goodwin
SARAH MAXWELL:
To get a comment on what Dr. Paz-Ares had to say, Peter attended an ASCO press briefing about the IMforte trial. It was chaired by ASCO’s Chief Medical Officer and Executive Vice President: Julie Gralow, who gave her reactions:
COMMENT: Julie Gralow MD FACP FASCO
Julie Gralow of the American Society of Clinical Oncology, adding her thoughts to what Luis Paz-Ares told us about the IMforte trial results in patients with small-cell lung cancer. And that’s all from this edition of the Audio Journal of Oncology. From me, Sarah Maxwell, goodbye.
ASCO ABSTRACT TITLE
“Lurbinectedin (lurbi) + atezolizumab (atezo) as first-line (1L) maintenance treatment (tx) in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC): Primary results of the phase 3 IMforte trial.”
https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.8006
https://www.audiomedica.com/wp-content/2025/06/Luis-Paz-Ares-PRODUCTION-MASTER-1-1.mp3
An interview with:
Elena Elez MD PhD, Vall d’Hebron Institute of Oncology, Barcelona, Spain
CHICAGO, USA—Adding the BRAF inhibitor encorafenib (partnered with EGFR-inhibitor cetuximab) to standard chemotherapy as initial therapy markedly delayed progression and extended life in patients whose inoperable metastatic colorectal cancers had tested positive for the BRAF V600E (found in around ten per cent of patients). This was in the randomized open label phase three BREAKWATER study reported at the 2025 Annual Meeting of the American Society of Clinical Oncology (ASCO).
After the ASCO conference, the Audio Journal of Oncology’s correspondent Peter Goodwin asked study leader Elena Elez from the Vall d’Hebron Institute of Oncology in Barcelona for the details.
INTERVIEW with Elena Elez MD PhD, Vall d’Hebron Institute of Oncology, Barcelona
ASCO ABSTRACT:
LBA3500: “First-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer (BREAKWATER): Progression-free survival and updated overall survival analyses”
Background:
BREAKWATER (NCT04607421) is an open-label, global, randomized, phase 3 study evaluating first-line (1L) encorafenib + cetuximab (EC) ± chemotherapy (chemo) vs standard of care (SOC; chemo ± bevacizumab) in BRAF V600E-mutant metastatic colorectal cancer (mCRC). The study previously met one of its dual primary endpoints (EPs) demonstrating clinically meaningful and statistically significant improvement in confirmed objective response rate (ORR) by blinded independent central review (BICR) in the ORR subset. These results were the basis for the FDA accelerated approval of EC+mFOLFOX6 for BRAF V600E-mutant mCRC, including in the 1L, under Project Frontrunner. Here, we report the primary analysis of progression-free survival (PFS) by BICR, updated interim analysis of OS, updated safety, and other analyses.
Methods:
Eligible patients (pts) with untreated BRAF V600E-mutant mCRC were randomized 1:1:1 to receive EC, EC+mFOLFOX6, or SOC; EC arm enrollment was closed after a protocol amendment. Dual primary EPs: ORR and PFS by BICR (EC+mFOLFOX6 vs SOC); key secondary EP: OS (EC+mFOLFOX6 vs SOC).
Results:
637 pts were randomized to EC, EC+mFOLFOX6, or SOC. Baseline demographics and disease characteristics were generally balanced between arms. EC+mFOLFOX6 (data cutoff: Jan 6, 2025) demonstrated a clinically meaningful and statistically significant PFS improvement vs SOC, meeting the other dual primary EP; HR = 0.53 (95% CI 0.407, 0.677; P < 0.0001); median PFS 12.8 vs 7.1 mo. OS was clinically meaningful and statistically significant vs SOC; HR = 0.49 (95% CI 0.375, 0.632; P < 0.0001); median OS 30.3 vs 15.1 mo. Median PFS and OS in the EC arm were 6.8 and 19.5 mo. These data and response data for all randomized pts are shown in the table. Serious treatment-emergent adverse events occurred in 30%, 46%, and 39% of pts in the safety analysis set. Safety was consistent with that known for each agent.
Conclusions: BREAKWATER demonstrated clinically meaningful and statistically significant PFS and OS improvements with EC+mFOLFOX6 vs SOC and manageable toxicities. EC+mFOLFOX6 is potentially practice changing as the new SOC.
An interview with: Yelena Y Janjigian MD, Medical Oncologist, Chief of Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York USA
CHICAGO—A treatment described as “practice-changing”, in which a combination of anti-PD-L1 immunotherapy and chemotherapy was used before and after surgery among patients with resectable gastric or gastroesophageal junction cancers, was reported from the MATTERHORN study at the Plenary Session of the 2025 Annual Meeting of the American Society of Clinical Oncology (ASCO).
First author, Medical Oncologist Yelena Y Janjigian MD, who is Chief of the Gastrointestinal Oncology Service at Memorial Sloan-Kettering Cancer Center in New York USA, discussed her findings and their clinical implications with the Audio Journal of Oncology’s Peter Goodwin:
INTERVIEW WITH Yelena Y Janjigian MD
ASCO ABSTRACT: LBA5 (Janjigian):
“Event-free survival in MATTERHORN: A randomized, phase 3 study of durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel chemotherapy (FLOT) in resectable gastric/gastroesophageal junction cancer (GC/GEJC).”
Background:
FLOT is a perioperative standard of care (SoC) in resectable GC/GEJC, yet recurrence rates remain high. Immune checkpoint inhibitors are approved in combination with chemotherapy in metastatic GC/GEJC, but not in the perioperative setting. The randomized, double-blind, global, Phase 3 MATTERHORN study (NCT04592913) assesses the combination of perioperative durvalumab (D) + FLOT vs placebo (P) + FLOT in participants (pts) with locally advanced, resectable GC/GEJC. The primary endpoint is EFS. Pathologic complete response (pCR) and overall survival (OS) are key secondary endpoints. The trial previously showed a statistically significant gain in pCR for D + FLOT. Here, we report efficacy and safety from the pre-planned interim analysis 2.
Methods:
Pts aged at least 18 years with histologically confirmed, resectable (Stage II–IVa per American Joint Committee on Cancer 8th edition) untreated G/GEJ adenocarcinoma were randomized 1:1 to D 1500 mg or P every 4 weeks (Q4W) on Day 1 + FLOT on
Days 1 and 15 for 4 cycles (2 cycles each neoadjuvant/adjuvant), followed by D 1500 mg or P on Day 1 Q4W for 10 cycles. Pts were stratified by Asia vs non-Asia, clinical lymph node status (positive vs negative) and programmed cell death ligand-1 Tumor Area Positivity score (at least 1% vs less than 1%). Data cutoff was Dec 20, 2024. EFS (time from randomization to progression, local or distant recurrence, or death) superiority for D + FLOT vs P + FLOT was assessed in all randomized pts by a stratified log-rank test (2-sided significance level threshold: 0.0239) on data according to RECIST v1.1 per BICR and/or locally by pathology testing.
Results:
In total, 948 pts were randomized to receive D + FLOT (n=474) or P + FLOT (n=474); median (m) follow up duration was 31.5 months (mo). Demographic/baseline characteristics were generally similar across treatment arms. D + FLOT demonstrated a statistically significant improvement in EFS vs P + FLOT (hazard ratio [HR] 0.71; 95% confidence interval [CI], 0.58–0.86; p,0.001), mEFS was not reached (NR) with D + FLOT vs 32.8 mo with P + FLOT. The 24-mo EFS rate was higher for D + FLOT vs P + FLOT (Table). mOS was NR for D + FLOT vs 47.2 mo for P + FLOT (HR 0.78; 95% CI, 0.62–0.97; p=0.025; 33.9% maturity) and will be formally assessed at the final analysis.
Maximum Grade 3 or 4 adverse event rates were similar between treatment arms; D + FLOT did not delay surgery or initiation of adjuvant therapy vs P + FLOT. Conclusion:
D + FLOT demonstrated a statistically significant improvement in EFS vs P + FLOT in pts with resectable GC/GEJC, with an encouraging OS trend. These results support D + FLOT as a potential new global SoC for resectable GC/GEJC. C
An interview with:
Christopher Booth, MD, FRCPC
Medical Oncologist and Professor, Queen’s University, Kingston, Canada
Comments from:
Rebecca Dent MD MSc,
Senior Consultant Medical Oncologist, Deputy Chief Executive Officer, National Cancer Centre, Singapore
CHICAGO— For patients with stage III and high-risk stage II colon cancer, a structured exercise program following surgery and adjuvant chemotherapy reduced the risk of recurrent or new cancer and increased survival in a study reported at the 2025 Annual Meeting of the American Society of Clinical Oncology. The long-term, large, randomized phase three Canadian Cancer Trials Group CO.21 CHALLENGE study found that post-treatment exercise was both achievable and effective and brought benefits rivalling those of new cancer medicines.
Study leader Christopher Booth MD FRCPC, a medical oncologist and professor at Queen’s University in Kingston, Canada, told the Audio Journal of Oncology’s Peter Goodwin about his group’s findings and conclusions.
Rebecca Dent MD MSc, Senior Consultant Medical Oncologist and Deputy Chief Executive Officer at the National Cancer Centre, Singapore, added her comments.
AUDIO JOURNAL OF ONCOLOGY:
Interviews with Christopher Booth and Rebecca Dent
ASCO 2025 ABTRACT
Abstract LBA3510:
A randomized phase III trial of the impact of a structured exercise program on disease–free survival (DFS) in stage 3 or high-risk stage 2 colon cancer: Canadian Cancer Trials Group (CCTG) CO.21 (CHALLENGE)
An interview with: Frank A Sinicrope, MD, Medical Oncologist, Mayo Clinic, Rochester, Minnesota.
CHICAGO —Big gains in survival have been reported among patients with stage three, node-positive colon cancer whose tumors tested positive for deficient mismatch repair.
At the American Society of Clinical Oncology 2025 Annual Meeting Frank Sinicrope reported findings from the phase three ATOMIC trial in which the immune checkpoint inhibitor atezolizumab was added to adjuvant chemotherapy after resection.
He discussed the study results with Audio Journal of Oncology correspondent Peter Goodwin:
INTERVIEW: Frank A Sinicrope MD, Mayo Clinic, Rochester, Minnesota
ASCO Abstract LBA1:
“Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III deficient DNA mismatch repair (dMMR) colon cancer (Alliance A021502; ATOMIC)”
An interview with:
Andy Zeng, MD/PhD candidate, University of Toronto and Princess Margaret Cancer Centre, Toronto, Canada
With comment from:
Hussein A Abbas MD PhD, Assistant Professor, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston TX
CHICAGO—A research study using single-cell RNA sequencing data has created a new gene expression atlas that shows how normal hematopoietic cells differentiate. Findings reported at the 2025 Annual Meeting of the American Association for Cancer Research (AACR) describe how it’s been used to catalog the multiple ways that aberrant differentiation can lead to acute myeloid leukemia (AML).
By using the study to provide a reference for normal hematopoietic cell differentiation the researchers have identified novel acute myeloid leukemia cell states that have potential therapeutic implications. It is hoped to shed light on how AML driver genes affect cell differentiation in different contexts, with the aim of informing new biomarkers and drug targets and helping AML researchers to address new hypotheses.
Lead author, Andy Zeng, who is a candidate for MD and PhD at University of Toronto and Princess Margaret Cancer Centre, Toronto, Canada, discussed the findings with Audio Journal of Oncology correspondent, Peter Goodwin, who also talked with hematologic malignancy clinician, who was not an author of the study, Hussein A Abbas MD PhD, Assistant Professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, Texas.
SARAH MAXWELL:
There’s new hope for understanding more about the malignant transformation of hematopoietic cells into acute myeloid leukemia. I’m Sarah Maxwell with the Audio Journal of Oncology.
At the 2025 Annual Meeting of the American Association for Cancer Research in Chicago, Canadian researchers reported on the use of single cell RNA sequencing to investigate molecular mechanisms leading to cancer, in patients at risk of AML. At the conference, Peter Goodwin got the details from lead author Andy Zeng from the Princess Margaret Cancer Centre in Toronto:
INTERVIEW: Andy G. X. Zeng
Peter was talking with Andy Zeng from the University of Toronto and Princess Margaret Cancer Centre in Canada.
And to get a comment on this, Peter talked with clinical oncologist Hussein Abbas, Assistant Professor in the Department of Leukemia, at the University of Texas MD Anderson Cancer Center in Houston.
INTERVIEW: Hussein Abbas
And Peter’s conversation at the AACR Annual Meeting with Hussein Abbas brings this edition of the Audio Journal of Oncology to an end. We’ll be back with more breaking news for cancer professionals very soon. I’m Sarah Maxwell.
AACR ABSTRACT:
“Single-cell transcriptional mapping reveals genetic and non-genetic determinants of aberrant differentiation in AML”
An interview with:
Yelena Y Janjigian MD, Medical Oncologist, Chief of Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York.
CHICAGO, USA—Patients with early-stage solid cancers with DNA mismatch repair-deficiency (also known as microsatellite instability) benefitted greatly if they received anti-programmed death-1 (PD-1) immunotherapy with pembrolizumab after surgery and standard of care if they tested positive for circulating tumor DNA (ctDNA).
These findings come from a phase two clinical trial reported at the 2025 Annual Meeting of the American Association for Cancer Research. Audio Journal of Oncology correspondent Peter Goodwin talked with first author of the study: Yelena Y Janjigian MD, Chief of the Gastrointestinal Oncology Service at Memorial Sloan-Kettering Cancer Center in New York.
INTERVIEW: Yelena Y Janjigian, MD
AACR ABSTRACT Title:
Circulating tumor DNA status to direct adjuvant immunotherapy for mismatch repair deficient tumors
The Audio Journal of Oncology talks with:
Paolo Marchetti MD, Scientific Director, Istituto Dermatopatico dell’Immacolata, Rome
And with:
Elaine R. Mardis, PhD FAACR, Co-Executive Director of the Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Rasmussen Nationwide Foundation Endowed Chair in Genomic Medicine, Professor of Pediatrics, Ohio State University College of Medicine, Columbus OH, USA.
CHICAGO, USA—Using a combination of tissue biopsy together with liquid biopsy seems to be the best way of providing samples for genomic profiling when you need to plan treatment for patients with advanced solid tumors. This is the clear implication of findings from the phase two multicenter ROME trial reported at 2025 Annual Meeting of the American Association for Cancer Research (AACR).
These two modalities of biopsy collect tissues from different parts of the tumor. So, an actionable mutation may be found by one method, and missed by another. But in cases where both methods detect the same targetable molecular marker, the strategy for treatment is now looking much clearer, according to the lead study author Paolo Marchetti, Scientific Director of the Istituto Dermatopatico dell’Immacolata in Rome. He’s been talking with our reporter in Chicago, Peter Goodwin, who also spoke with the AACR press briefing moderator Elaine R Mardis PhD FAACR, Co-Executive Director of the Rasmussen Institute for Genomic Medicine at Nationwide Children’s Hospital, who holds the Chair in Genomic Medicine and is Professor of Pediatrics at Ohio State University College of Medicine in Columbus Ohio.
INTERVIEWS:
- Paolo Marchetti MD, Scientific Director, Istituto Dermatopatico dell’Immacolata, Rome
- Elaine R. Mardis,PhD FAACR, Co-Executive Director of the Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Rasmussen Nationwide Foundation Endowed Chair in Genomic Medicine, Professor of Pediatrics, Ohio State University College of Medicine, Columbus OH.
- AACR Abstract Title:
Combined tissue and liquid biopsy improves outcomes in advanced solid tumors: an exploratory analysis of the ROME trial.
An Interview with:
Stephen Strickland, Jr. MD MSCI, Director, Leukemia Research; Executive Chair, Leukemia Research Committee, Sarah Cannon Research Instiute, Nashville, Tennessee USA
CHICAGO – Several patients with acute myeloid leukemia, who were treated with SENTI-202, a first-in-class chimeric antigen receptor (CAR) natural killer (NK) cell therapy, experienced complete remission after not responding to (or having relapsed following) prior treatments, according to interim results from the phase one SENTI-202-101 clinical trial reported at the 2025 Annual Meeting of the American Association for Cancer Research.
During the conference Audio Journal of Oncology correspondent Peter Goodwin met up with the lead author of the study, Stephen Strickland, Jr. MD MSCI, Director of Leukemia Research and Executive Chair of the Leukemia Research Committee at the Sarah Cannon Research Institute in Nashville, TN.
AACR Abstract title:
First-in-human, multicenter study of SENTI-202, a CD33/FLT3 selective off-the-shelf logic gated CAR NK cell therapy in hematologic malignancies including AML: Clinical data
An interview with:
Adetunji T. Toriola, MD, PhD, MPH, Professor of Surgery, Department of Surgery and Division of Public Health Sciences, Washington University School of Medicine and Siteman Cancer Center, St Louis, Missouri, USA
And with:
Elaine R. Mardis, PhD FAACR, Co-executive director of the Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Rasmussen Nationwide Foundation Endowed Chair in Genomic Medicine, Professor of Pediatrics, Ohio State University College of Medicine, Columbus OH.
CHICAGO, USA—Breast cancer mortality in American women aged 20-49 dropped significantly between 2010 and 2020, according to research reported at the American Association for Cancer Research 2025 Annual Meeting by epidemiologists from St Louis, Missouri. This was despite a rising incidence of the disease in these younger women.
Peter Goodwin met up with the presenting author of the study, Adetunji T. Toriola MD PhD MPH, Professor of Surgery at Washington University School of Medicine and the Siteman Cancer Center in St Louis.
Elaine Mardis PhD, Co-Executive Director of the Rasmussen Institute for Genomic Medicine and Nationwide Children’s Professor of Pediatrics at Ohio State University College of Medicine, in Columbus, added her comments.
AACR Abstract Title:
“Trends in breast cancer incidence-based mortality among US women aged 20-49 by molecular subtypes and race”
An interview with:
Adam Thiesen, PhD Candidate, UConn Health, University of Connecticut and the Jackson Laboratory for Genomic Medicine, Farmington, CT
And with:
Jayesh Desai MD, Medical Oncologist, Associate Director Clinical Research, Peter MacCallum Cancer Centre, Melbourne, Australia, Co-Chair, AACR Clinical Committee.
CHICAGO – An artificial intelligence-based model accurately classified pediatric sarcomas using histopathology images alone, according to study conclusions reported to the American Association for Cancer Research 2025 Annual Meeting.
The researchers said it could help provide more patients access to quick, streamlined, and highly accurate cancer diagnoses regardless of their geographic location or health care setting.
Audio Journal of Oncology correspondent Peter Goodwin met up with first author of the study, Adam Thiesen, who is a PhD Candidate at UConn Health, University of Connecticut and the Jackson Laboratory for Genomic Medicine in Farmington, Connecticut.
For expert comment, Peter Goodwin also talked with Jayesh Desai MD, Associate Director Clinical Research, Peter MacCallum Cancer Centre, Melbourne, Australia.
AACR ABSTRACT Title:
“Automated classification of pediatric sarcoma using digital histopathology”
An interview with:
John V Heymach MD PhD, Professor and Chair of Thoracic/Head and Neck Medical Oncology, Ruth Legett Jones Distinguished Chair, University of Texas MD Anderson Cancer Center, Houston TX
And with:
Jayesh Desai MD, Medical Oncologist, Associate Director Clinical Research, Peter MacCallum Cancer Centre, Melbourne, Australia, Co-Chair, AACR Clinical Committee.
CHICAGO, USA—A safer way of targeting tumors with mutated human epidermal growth factor receptor 2 (HER2) in patients with previously treated non-small cell lung cancer was discussed at the 2025 Annual Meeting of the American Association for Cancer Research, in Chicago.Promising clinical benefits were reported from the Beamion LUNG-1 trial, in which patients were treated with the anti-HER2 tyrosine kinase inhibitor zongertinib that doesn’t affect the epidermal growth factor receptor (EGFR).
Audio Journal of Oncology correspondent Peter Goodwin met up with the study’s presenting author John V Heymach MD PhD, Chair of Thoracic/Head and Neck Medical Oncology, at the University of Texas MD Anderson Cancer Center in Houston, and with Jayesh Desai MD, Medical Oncologist at the Peter McCallum Cancer Centre in Melbourne Australia, Co-Chair of the AACR Clinical Committee, who moderated a press briefing held to discuss the findings of the Beamion LUNG-1 study.
An interview with:
Andrea Cercek MD, Gastrointestinal Cancer Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York
And:
Ryan B Corcoran MD PhD, Director of the GI Cancer Program, Massachusetts General Hospital Cancer Center, Boston MA
CHICAGO—The Audio Journal of Oncology reports on the neoadjuvant use of programmed cell-death protein 1 (PD-1) immune checkpoint inhibition to give patients whose resectable colorectal cancers express mismatch repair deficiency the option of avoiding surgery. Early results from a phase two trial with the PD-1 blocker dostarlimab were reported at the 2025 Annual Meeting of the American Association for Cancer Research held in Chicago.
At the meeting the Audio Journal’s correspondent Peter Goodwin met up with the study first author, Andrea Cercek MD, a gastrointestinal cancer medical oncologist from Memorial Sloan Kettering Cancer Center in New York.
AACR Abstract title:
“Non operative management of mismatch repair deficient tumors”
An interview with:
Anisha B Patel MD, Associate Professor of Dermatology, Division of Internal Medicine, MD Anderson Cancer Center, Houston TX
CHICAGO, USA—Acneiform rash toxicities caused by anti- epidermal growth factor receptor (EGFR) therapies were markedly reduced among patients with colorectal cancer in a double-blind placebo-controlled, randomized phase two clinical trial that assessed the efficacy of a topical BRAF inhibitor gel designed to treat these skin lesions without affecting cancer treatment.
The results were presented at the 2025 Annual Meeting of the American Association for Cancer Research (AACR).
First author of the study, Anisha Patel MD, Associate Professor of Dermatology at the MD Anderson Cancer Center in Houston Texas, gave Audio Journal of Oncology correspondent Peter Goodwin more details about the findings
AACR Abstract Title:
“A double-blind placebo-controlled randomized phase 2 clinical trial to assess the efficacy of a topical BRAF inhibitor for acneiform rash toxicities from anti-EGFR therapies”
Interviews with:
Ravindra Uppaluri, MD PhD, Director of Head and Neck Surgical Oncology, Dana Farber Brigham Cancer Center, Boston MA;
And: Ryan B Corcoran MD PhD, Director of the gastrointestinal cancer program, Massachusetts General Hospital Cancer Center, Associate Professor of Medicine Harvard Medical School and Co-Chair of the American Association for Cancer Research Clinical Trials Committee.
CHICAGO, USA—Perioperative immunotherapy, using the PD-1 blocker pembrolizumab both before and after surgery, has been investigated in patients with newly diagnosed head and neck cancers in the phase three KEYNOTE-689 study. Findings were reported at the 2025 Annual Meeting of the American Association for Cancer Research.
Audio Journal of Oncology correspondent Peter Goodwin met up with lead investigator Ravindra Uppaluri MD PhD, Director of Head and Neck Surgical Oncology at the Dana Farber Brigham Cancer Center in Boston MA and Ryan B Corcoran MD PhD, Director of the gastrointestinal cancer program at Massachusetts General Hospital Cancer Center and Co-Chair of the American Association for Cancer Research Clinical Trials Committee.
AACR Abstract Title:
“Neoadjuvant and adjuvant pembrolizumab plus standard of care (SOC) in resectable locally advanced head and neck squamous cell carcinoma (LA HNSCC): Phase 3 KEYNOTE-689 study”
An interview with: Kathryn C Arbour MD, Thoracic Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York USA
And: Ryan B Corcoran MD PhD, Massachusetts General Cancer Center, Associate Professor of Medicine Harvard Medical School, Co-Chair, American Association for Cancer Research Clinical Trials Committee
CHICAGO, USA— The four per cent of patients with previously treated non-small cell lung cancer whose tumors harbor a KRAS G12D mutation may soon have an effective targeted treatment: currently an unmet need. Clinical benefit from the oral KRAS G12D inhibitor zoldonrasib is reported in findings presented at the 2025 American Association for Cancer Research (AACR) Annual Meeting.
First author of the research Kathryn C Arbour MD, from Memorial Sloan Kettering Cancer Center in New York, told Audio Journal of Oncology correspondent Peter Goodwin how the drug’s ability to target both active and inactive conformations of the KRAS G12D oncogene could help overcome treatment resistance.
Ryan B Corcoran MD PhD, from the Massachusetts General Cancer Center and Harvard University, Co-Chair of the AACR Clinical Trials Committee, who was not involved with the research, adds his comments on the clinical implications for treating solid tumors harboring the RAS G12D mutation.
AACR 2025 Abstract Title:
“Preliminary safety and antitumor activity of zoldonrasib (RMC-9805), an oral, RAS(ON) G12D-selective, tri-complex inhibitor in patients with KRAS G12D non-small cell lung cancer (NSCLC) from a phase 1 study in advanced solid tumors”
An interview with:
Jiafu Ji MD PhD DrPH FRCS, Fellow of the Chinese Academy of Medical Science, Professor and Chief, Gastrointestinal Cancer Center, Peking University Cancer Hospital, Beijing Institute for Cancer Research, Beijing, China
Sarah Maxwell, Audio Journal of Oncology:
The idea of harnessing two different pathways of checkpoint inhibition simultaneously is very appealing for the treatment of high-risk gastric cancers. But a research team in China, proposed that, blocking both the PD-1 and CTLA-4 pathways, within a single bi-specific agent, as a component of initial therapy, was potentially a better way to do this than to use a combination of two individual checkpoint inhibitors.
At the 2024 American Association for Cancer Research annual meeting in San Diego, Jiafu Ji, from the Beijing Institute for Cancer Research, reported his group’s findings from the COMPASSION-15 trial, with 610 patients who had untreated, unresectable, HER2-negative, locally advanced or metastatic gastric cancer, using the bi-specific agent, cadonilimab, together with standard chemotherapy. After his talk he discussed with us the rational for this approach and the promising clinical findings:
Jiafu Ji, MD, PhD, DrPh, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, the Beijing Key Laboratory of Carcinogenesis and Translational Research, and the Gastrointestinal Cancer Center, Beijing Cancer Hospital, Beijing, China
IN: “Gastric cancer is a leading cause of death in China………
OUT………American Association for Cancer Research, I’m Peter Goodwin”
10:13 secs
AACR ABSTRACT
Cadonilimab plus chemotherapy versus chemotherapy as first-line treatment for unresectable locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (COMPASSION-15): A randomized, double-blind, phase 3 trial
An interview with:
Ajay Goel PhD, Chair of the Molecular Diagnostics and Experimental Therapeutics Department, Beckman Research Institute, City of Hope, Los Angeles California.
SAN DIEGO—The prospect of detecting pancreatic cancer at very early stages, when cure may be possible, is now being held out by research showing that the sub-cellular molecules called “exosomes” (shed into the bloodstream by cancer cells) can be analyzed to get very early diagnosis of the disease.
Study results using liquid biopsy to test for exosomes were reported at the 2024 American Association for Cancer Research Annual Meeting in San Diego. After his talk at the conference the senior author of the research, Ajay Goel, who is Chair Molecular Diagnostics and Experimental Therapeutics at the Beckman Research Institute, in City of Hope, Los Angeles, called in to Audio Journal of Oncology studio to tell us more about this exciting new science and its clinical implications:
Sarah Maxwell, Audio Journal of Oncology:
“A new non-invasive test, for pancreatic cancer, from liquid biopsy, could soon make it possible to detect the disease at stages when early intervention could greatly extend life, and even make cure possible. The tests checks for the presence of “exosomes” — circulating fragments of cancer cells — that can give early warning of a developing tumor.
At the American Association for Cancer Research Annual Meeting in San Diego, The Audio Journal of Oncology heard from Ajay Goel, senior author of the study who is Chair of the Molecular Diagnostics and Experimental Therapeutics Department at City of Hope in Los Angeles CA.
Ajay Goel PhD, Chair of the Molecular Diagnostics and Experimental Therapeutics Department, Beckman Research Institute, City of Hope, Los Angeles California:
IN: “Exosomes are essentially small extra-cellular vesicles released by the cancer cells………OUT: ……here in San Diego at the American Association for Cancer Research.” 13:09 secs.
AACR Abstract TITLE:
“An exosome-based liquid biopsy for non-invasive, early detection of patients with pancreatic ductal adenocarcinoma: A multicenter and prospective study”
An interview with: Sundar Jagannath MBBS, Professor of Medicine, Hematology and Medical Oncology, Director of the Center of Excellence for Multiple Myeloma, Icahn School of Medicine, Mount Sinai, New York.
Sarah Maxwell, Audio Journal of Oncology:
“An exciting, new immunotherapy treatment for multiple myeloma, was under discussion at the 2024 American Association for Cancer Research Annual Meeting, held in San Diego. It was with a drug that targets not one but two cells to fight the disease.
The agent, linvoseltamab, is a B-cell maturation antigen-targeted, T-cell-engaging, bispecific antibody. A multi-center international study, reported at the conference that patients with relapsed or refractory multiple myeloma, had robust clinical benefit from treatment with the drug. And that included those in difficult-to-treat subgroups.
After giving his talk in San Diego, lead author Sundar Jagannath, Director of the Center of Excellence for Multiple Myeloma, at Mount Sinai in New York, gave the Audio Journal of Oncology more details on the therapeutic benefits the drug offers. He began by talking about where this new approach fits into the landscape and history of treatments for multiple myeloma:
Audio Journal of Oncology interview with: Sundar Jagannath MBBS, Director of the Center of Excellence for Multiple Myeloma, Icahn School of Medicine, Mount Sinai, New York.
IN: I’ve been in the field of multiple myeloma….…
OUT: ….in New York. I’m Peter Goodwin.
15:43”
AACR Abstract Title:
Linvoseltamab, a B-cell maturation antigen-targeted T-cell-engaging bispecific antibody, induces deep and durable responses in patients with relapsed or refractory multiple myeloma including difficult-to-treat subgroups
https://www.abstractsonline.com/pp8/#!/20272/presentation/11419
An interview with:
Olivier Lantz MD PhD, Head of the Clinical Immunology Laboratory, Institut Curie, Paris, France
PARIS, France—A clinical trial using a personalized therapeutic vaccine, that recognizes multiple genetic features of each patient’s tumor, brought durable tumor-specific immune responses in patients with surgically resected HPV-negative head and neck squamous cell cancers, and also prevented relapse in some patients.
At the 2024 Annual Meeting of the American Association for Cancer Research, held in San Diego, California, Olivier Lantz MD PhD, Head of the Clinical Immunology Laboratory at the Institut Curie in Paris, gave the Audio Journal of Oncology the latest update on his findings with the “neoantigen vaccine”.
AACR 2024 Abstract Number: LB401
ABSTRACT TITLE: Personalized vaccine TG4050 induces polyepitopic immune responses against private neoantigens in resected HPV negative head and neck cancers
SAN ANTONIO, USA—Women with hormone receptor positive HER-2 negative breast cancer and Oncotype DX recurrence scores above 31 could benefit from having anthracycline therapy added to their taxane-based chemotherapy, according to breast medical oncologist and assistant professor of internal medicine, Nan Chen MD, from the University of Chicago.
She reported her group’s latest analysis of records from 2,528 patients in the TAILORx trial at the 2024 San Antonio Breast Cancer Symposium comparing patients being treated after surgery with taxane/cyclophosphamide chemotherapy with or without additional anthracycline. After her talk she discussed the findings with Peter Goodwin:
SAN FRANCISCO, CA—Adding the poly ADP ribose polymerase (PARP) inhibitor drug talazoparib to standard anti-androgen therapy with enzalutamide statistically significantly extended overall survival among patients whose metastatic castration resistant prostate cancers had specific molecular markers.
This finding was reported at the 2025 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium held in San Francisco from the TALAPRO-2 phase three clinical trial investigating patients with or without homologous recombination repair (HRR) gene alterations.
The co-lead author of the study, Karim Fizazi MD PhD, Head of the Genitourinary Oncology Group at the Gustave Roussy Institute in Paris and Professor of Oncology at the Université Paris-Saclay in Paris, France, talked with Audio Journal of Oncology correspondent Peter Goodwin about the details of the findings and his clinical recommendations.
Audio Journal of Oncology
Patients with Desmoplastic Melanoma Were Exceptional Responders to Single Agent Pembrolizumab
LOS ANGELES, CA—Single agent immunotherapy with the anti-programmed death-1 (PD-1) agent pembrolizumab resulted in markedly high melanoma-specific survival rates among patients with either resectable or metastatic desmoplastic melanoma in a study reported to the American Association for Cancer Research 2025 Immno Oncology conference.
Lead researcher Kari L Kendra MD PhD, Director of the Cutaneous Oncology Program and Chair of the Melanoma Disease Specific Committee at Ohio State University’s Wexner Medical Center in Columbus, OH gave the Audio Journal of Oncology’s Peter Goodwin the latest details:
Bilateral Mastectomy and Salpingo-Oophorectomy Significantly Extend Survival In BRCA-mutation Carriers Who Already Have Breast Cancer
The important question of whether to recommend risk-reducing surgery to patients who are carriers of pathogenic mutations in either BRCA1 or BRCA2 genes (or both), and have already developed breast cancer, has been investigated in a study from Italy reported at the 2025 San Antonio Breast Cancer Symposium.
Researcher Matteo Lambertini MD PhD, from the University of Genoa, Assistant Professor and Consultant in Medical Oncology at the San Martino IST Hospital in Genoa, Italy, gave the details to Audio Journal of Oncology correspondent Peter Goodwin.
SABCS ABSTRACT TITLE:
“Association between risk-reducing surgeries and survival in young BRCA carriers with breast cancer: results from an international cohort study”
https://sabcs.org/Portals/0/Documents/Embargoed/GS1-08%20Embargoed.pdf?ver=9pxlvFm0NKFNPmAgpDr1-Q%3d%3d
SAN ANTONIO, USA—In patients with hormone receptor-positive, HER2-negative, low-risk ductal carcinoma in situ (DCIS) active monitoring, compared with surgery, resulted in no difference in terms of cancer outcomes in the multicenter, randomized COMET study that compared oncologic outcomes of patients randomized to guideline-concordant care (with surgery alone or with radiation therapy) or active monitoring. COMET investigated 995 patients with grade one or two DCIS with no evidence of invasive cancer.
After reporting the findings at the 2024 San Antonio Breast Cancer Symposium, study author E. Shelley Hwang MD MPH, Breast Surgeon and Director of the Breast Oncology Program at Duke University gave more details to Audio Journal of Oncology Editor, Peter Goodwin:
PODCAST EPISODE:
Audio Journal of Oncology interview with E. Shelley Hwang MD MPH
2024 San Antonio Breast Cancer Symposium ABSTRACT：
GS2-05: Early Oncologic Outcomes Following Active Monitoring or Surgery (+/- Radiation) for Low Risk DCIS: the Comparing an Operation to Monitoring, with or without Endocrine Therapy (COMET) Study (AFT-25)
BRIGHTON, UK—In underserved communities throughout the world low rates of early breast cancer detection are key drivers of mortality, according to the findings of research from Uganda, the United Kingdom and Nigeria. A range of low cost community-based interventions could be used to modify these drivers, the research concludes.Huge reductions of breast cancer mortality in underserved communities could be achieved by prioritizing early detection, according to lead author Deborah Ikhile PhD, from the Brighton and Sussex Medical School at the University of Brighton in Sussex UK, who discussed the implications of her findings with the Audio Journal of Oncology's Peter Goodwin at the Royal Society of Medicine’s 2023 Tackling Inequalities conference. This could be achieved—even where costly mass screening was not possible—by health education delivered through existing social and cultural structures that were presently being overlooked or ignored, her study concluded.“Breast cancer is beyond an individual disease,” said Dr. Ikhile. “Doctors, researchers, clinicians, decision-makers need to have in-depth understanding of the social determinants that influence a woman’s ability to present early or not.”Her group’s five-year survey with structured interviews among women in rural and semi-rural communities of Uganda had concluded that ‘structural violence’ was a root cause of late breast cancer detection.This consisted of multiple disservices to women, unintentionally perpetrated through inappropriate medical care structures. Poor health education plus myopic national, global and donor priorities, all combined with negative attitudes to women, and a failure to engage with the well-established grass-roots local organizations in the community.According to Dr. Ikhile, existing local services and social infrastructures could be harnessed to turn around breast cancer detection.The present-day two-fold excess of mortality from breast cancer among most black African women everywhere (as compared their white counterparts in privileged communities) could largely be eliminated by effective early detection. It was necessary to overcome factors such as stigma, misogyny, fear and gender prejudice from the global level downwards. She believed Uganda was not exceptional and that the findings were relevant to cancer detection in underserved communities everywhere.Dr. Ikhile’s interest in getting to the bottom of breast cancer inequalities began when she was still living in Nigeria and had (what turned out to be) a benign breast lump. Because she had access to private medicine her parents were able to get prompt diagnosis, followed by surgical excision. But this sensitized her to the plight of millions of women in low-resourced communities who did not have access to private health care.The research in Uganda sought to identify the challenges and barriers to breast cancer detection and to investigate how these issues could be addressed within a primary care context.The findings showed that cancer in Uganda was beyond individual control. “What came out is that, beyond your lack of knowledge, your lack of awareness, beyond fear, beyond attitude: Other factors, like community support, primary care services, even the clinician’s pressures, all these factors come into play, and support us to look at a holistic view to breast cancer detection,” Dr. Ikhile said. The survey also found that even after eventual detection of breast cancer there was often no easy access to follow-up care and services.The whole agenda surrounding campaigns such as the Early Detection Saves Lives initiative had been flawed, as these had often centered around victim-blaming—making it seem as though the women were responsible for not detecting breast cancer early. But this was not a reality for most women, according to Dr. Ikhile. “The reality for women is that they want to know. They felt disempowered because of the lack of knowledge.”“What came out of the interviews was a lack of awareness: Of what breast cancer is, of the signs and symptoms, even the risk factors, and even how to go for screening, how to detect breast cancer. And fear actually came up as a huge issue. They saw cancer as a death sentence, like: If I get breast cancer I’m going to die.”Dr. Ikhile also highlighted the issue of stigma. Women were afraid to go to national cancer screening services for fear of being stigmatized as cancer victims, she said. “So, even if screening were organized they would not go, just because of that perception of being assumed to have cancer.”Dr. Ikhile’s research uncovered a very low level of knowledge about breast cancer and what to do if you suspected you had it, she said. This was very different from the UK where she had studied black African women living in a typical city in the English Midlands, Nottingham.“They were generally aware of breast cancer,” she said. This was a stark contrast to some of the local communities she had studied in Uganda, where she learned there was not even a local word for breast cancer. “So even [with the signs] they really don’t know what disease it is, because they don’t understand what it means in the local language.” And fatalism contributed to lack of action against breast cancer, often linked to spiritual or religious beliefs.When she was asked to explain what structural violence consisted of in the study community, Ikhile said the concept of structural violence looked at the way government and local service structures were partnered to help perpetuate the health or sickness of individuals.“There were a lot of underlying factors. It is not enough to say that a woman does not know enough about breast cancer. It is not enough to say a woman has fear,” she said. “So, the study sought to find what perpetuated that fear, and what were the underlying factors promoting or influencing that lack of knowledge.”“One of the factors that came out was that there was no cancer policy in the country. Uganda did not have any national cancer policy at the time of the study.” This resulted in no national strategy or direction to guide how cancer should be controlled in the country.Medical priorities were also found to be inappropriate for breast cancer. For one thing communicable diseases were in competition with cancer for resources. To make matters worse, most of the priorities in Uganda were driven by international donors, said Dr. Ikhile, which—despite being well-intentioned—were not sufficiently well-informed about the true needs of the people. For example: Funding for HIV would inevitably prioritize HIV and donors targeting cardiovascular disease would similarly not have cancer in their sights. Breast cancer was clearly being overlooked.Even donor funding for breast cancer could overlook early detection among widely spread—often rural—communities, in favor of breast cancer treatments which were not even appropriate for many patients with the late stages of breast cancer frequently forming the majority of those eventually diagnosed in these underserved communities.And the benefit of costly screening programs had to be questioned, according to Ikhile, who favored education programs.“What is important is knowing your breast,” she said. This was in a context of the study findings that most women interviewed did not even know that breast lumps could be a sign of breast cancer. And they were even being wrongly advised by primary care teams, who were also insufficiently knowledgeable about breast cancer. Women needed to know that any changes in their breasts indicated that they should find help.Gender norms and gender roles could also inhibit actions needed for detecting breast cancer, the study found. Traditional values about the place of women in society and deference to men could negatively influence breast cancer outcomes, particularly in rural communities.But there was a positive finding from the research. ”Sensitizing men as champions for women’s health could be a great motivator for women, wives, daughters, mothers, who could then seek care.”Awareness was the key to resolving these issues, said Dr. Ikhile. This needed to be among all members of the community: women, husbands, and health-care practitioners. “What is important is understanding the social and cultural environment and the factors that influence ability to seek or not to seek help.”She also stressed ‘cultural competence’ among doctors: “Knowing how to deliver care in a culturally competent manner, interacting with a woman in a way that won’t lead to fear. It is very important to know where your patient is coming from,” she said.Happily, in the case of African communities there were often strong social bonds and structures that were available to be harnessed, said Ikhile. “So, they can use those pathways to create awareness and use organizations like churches and community health workers who are trusted people. She also saw the need for doctors to be very much part of the community health awareness strategy, rather than being left in ivory towers to treat patients only after diagnosis.Dr. Ikhile regarded grass-roots understanding of the local communities, and engagement with local organizations, as bedrocks of a plan to achieve timely detection of breast cancer. “It is very important for donors to engage and work hand-in-hand with those actually on the ground to implement any of the projects,” she said.
Audio Journal of Oncology, February 14 2023, Reporting from the American Society of Hematology Annual Meeting (ASH), December 2022
An interview with Amy A. Kirkwood MSc, Senior Statistician at the Cancer Research UK & UCL Cancer Trials Centre, University College, London, UK
Interviewer: Peter M GoodwinTITLE: Options Identified for in Acute Lymphoblastic Leukemia
NEW ORLEANS, USA—A big study conducted over an extended period of time has shown that there is scope for reducing the intensity of chemotherapy for patients with acute lymphoblastic leukema (ALL) and (the rarer) lymphoblastic lymphoma (LBL). Modifications to standard protocols offer scope for sparing many children the potential toxicity of full-does standard regimens without compromising cure rates.
Amy Kirkwood, Chief Statistician from University College, London tells the Audio Journal of Oncology (AJO) about her group’s findings from the randomized phase three UKALL 2011 study, reported (at the American Society of Hematology (ASH) 2022 Annual Meeting), showing that adjustments to current multi-agent chemotherapy regimens brought changes in outcome. She concludes that more gentle treatments may be possible for many patients while maintaining or improving efficacy for those at high risk.
https://ashpublications.org/blood/article/140/Supplement%201/516/488151/High-Dose-Methotrexate-Does-Not-Reduce-the-Risk-of
The treatment of ALL had improved hugely in the last 50 years, first author Amy A. Kirkwood MSc, Senior Statistician at the Cancer Research UK & UCL Cancer Trials Centre, University College, London, UK, told the AJO after giving her report at ASH. “We now have about 95 percent survival. About 15 percent of children will relapse. But we know that 50 years ago we were curing about 50 per cent of people with half the treatment. So, we know that we are overtreating large numbers of children,” she said.
So, trials were now looking at treatment reductions, and at trying to identify high-risk patients to design new ways of improving efficacy for that group only, she said. “We want to try and decrease treatment for the majority who will do well,” Kirkwood noted.
Specifically, the trial found that using high-dose methotrexate (HDM) did not improve central nervous system (CNS) relapse—contrary to some expectations. According to the UKALL 2011 study findings, it may have improved bone marrow relapse for some sub-groups of patients with B-lineage disease, however.
The trial also found that with some chemotherapy regimens the addition of monthly “pulses” of vincristine and dexamethasone (in the maintenance phase of treatment) had been un-necessary. They proved to be “non-inferior” for bone marrow relapse—compared with the standard practice of including such pulses. This suggested that pulse-free treatment could potentially be an option for some patients.
Study details
The UKALL 2011 study allocated patients to study arms in accordance with their risks, as stratified by National Cancer Institute (NCI) risk, cytogenetics and “end of induction minimum residual disease” (MRD). The aim was to assess whether elements of treatment could potentially be de-escalated without loss of efficacy. Randomizations were allocated within the several different standard “blocks” of chemotherapy.
Firstly, in the “induction” block of chemotherapy (aiming to get rid of most of the disease) there was a randomization between two different dose schedules of dexamethasone. A short (higher) dose schedule was compared with standard dexamethasone dosing. The aim had been to look at whether steroid dose could influence the incidence of side effects. This was followed by the “consolidation” block all in which all patients were treated the same.
Kirkwood said they saw no difference from steroid dosing schedule changes. “We were hoping to see a difference in steroid-related morbidity and mortality, so that randomization [was] closed,” she said. And, there had also been some “worrying trends” that maybe the patients treated with a shorter dexamethasone schedule (higher dose) were relapsing more often, she commented.
The second randomization (in the “interim maintenance” phase of treatment) was between standard and high-dose methotrexate. Although this was looking primarily for any impact of methotrexate dose on CNS relapse (and had found: “No difference at all”) Kirkwood noted there had been an effect of methotrexate dose on bone-marrow relapse. “Overall, we didn’t see a difference. But we found an interaction between the first randomization (the short versus standard dexamethasone) and the high methotrexate dose randomization.” The results were different depending on which steroid dose a patient had received initially. “If you had short dexamethasone up-front, then the high-dose methotrexate didn’t improve your bone marrow relapse risk. But if you had the standard dexamethasone up front, it looked like it might improve your bone marrow relapse risk. And we don’t know what caused this,” she said.
After the next block of treatment (called “delayed intensification” in which all patients had the same therapy) the third randomization was during the “maintenance” treatment. Patients either did, or did not, receive the monthly “pulses” of vincristine and dexamethasone. Primarily, the aim had been to see if the pulses had any effect on the bone marrow relapse rate. “[It] was non-inferior. We saw a small decrease. But it was within our pre-specified margin of five percent,” said Kirkwood. The team concluded it had been safe to remove the pulses. “However, we did see a ‘bit of a decrease’ in terms of event-free survival—over the five percent limit,” she said.
In terms of practical recommendations coming out of the UKALL 2011 study Kirkwood noted that knowledge about safe and effective options for changing methotrexate dose had been clarified. “We found that the patients who had standard dexamethasone, standard interim maintenance, didn’t have high [methotrexate] dose, and then went on to have pulses, had very similar outcomes to those that had the high-dose methotrexate. So that may be a trade-off: that you give the high-dose, you don’t give the pulses. Or, you give our standard [dose and] you still give the pulses.”
“The removal of pulses is probably safe in some groups of patients, but we still need to do further analysis,” she said. “The vast majority of children will be cured with front-line therapy. And our protocols are now working hard to try and pull out those small groups patients that are going to do badly and make sure they get the treatment that is best for them.”
ASH ABSTRACT DETAILS:ABSTRACT 214High Dose Methotrexate Does Not Reduce the Risk of CNS Relapse in Children and Young Adults with Acute Lymphoblastic Leukaemia and Lymphoblastic Lymphoma. Results of the Randomised Phase III Study UKALL 2011Program: Oral and Poster AbstractsType: OralSession: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Clinical TrialsHematology Disease Topics & Pathways:Non-Biological therapies, Chemotherapy, Combination therapy, TherapiesSaturday, December 10, 2022: 2:45 PMAmy A. Kirkwood, MSc1, Nicholas Goulden, MD, PhD, MRCPath2, John Moppett, PhD FRCPath3, Sujith Samarasinghe, PhD, FRCPath4, Jon Mee5, Rachael Hough, MD FRCPath6, Pamela R. Kearns, PhD, FRCPC7, Sarah Lawson, MBBS FRCPath8, Clare J. Rowntree, MBBS PhD9* and Ajay Vora, MD101Cancer Research UK & UCL Cancer Trials Centre, University College London, London, United Kingdom2Great Ormond Street Hospital, London, United Kingdom3Department of Haematology, Bristol Children's Hospital, Bristol, United Kingdom4Department of Paediatric Haematology, Great Ormond Street Hospital for Children, London, United Kingdom5Cancer Clinical Trials Unit, Birmingham University, Birmingham, United Kingdom6University College Hospital, University College of London, London, United Kingdom7Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham, Birmingham, United Kingdom8Birmingham Children's Hospital, Birmingham, United Kingdom9Department of Haematology, University Hospital of Wales, Cardiff, United Kingdom10Department of Haematology, Great Ormond Street Hospital for Children, London, United KingdomIntroductionUKALL 2011 randomised children and young adults (up to 25) with Acute Lymphoblastic Leukaemia (ALL) or Lymphoblastic Lymphoma (LBL). The aims were to reduce induction toxicity (R1: Short [14 days] vs Standard [28 days] dexamethasone), CNS relapse risk (R2IM: HD MTX (HDM) vs standard interim maintenance (SIM)) and maintenance morbidity (R2pulses: Vincristine (VCR)/dexamethasone pulses or not). R1 results were presented at ASH 2017 and did not show a reduction in toxicity with short dexamethasone. Results of R2IM and R2pulses are reported here.Patients and MethodsPatients were stratified by NCI risk, cytogenetics and end of induction MRD to receive Regimens A (NCI standard risk, MRD low risk), B (NCI high risk, MRD low risk) or C (Cytogenetic poor risk or MRD intermediate risk regardless of NCI risk). MRD high risk (end of consolidation MRD >0.5%, n=14) were not eligible for randomisation and received off protocol therapy. R2 was a factorial randomisation stratified by factors including NCI and MRD risk groups and resulted in 4 arms: HDM with pulses, HDM without pulses, standard interim maintenance (SIM) with pulses (standard of care) and SIM without pulses. SIM was for 2 months with oral mercaptopurine/MTX, monthly pulses and single IT MTX in Regimens A and B, and 5 doses of escalating IV MTX (Capizzi) + VCR + 2 doses of Pegylated asparaginase in Regimen C. HDM was given at a dose of 5g/m2 x 4 doses 2 weeks apart, low dose 6-MP and 2 doses of Pegylated asparaginase (Regimen C only). The primary endpoint for R2IM was the CNS relapse rate (CNSR) and for R2pulses was the bone marrow relapse rate (BMR) in ALL only; non-inferiority, 5% margin at 5 years. Event Free Survival (EFS) was considered a primary endpoint for both.ResultsOf the 2750 patients registered on trial between April 2012 and December 2018, 1902 were randomised to R1 (closed April 2017) and 1570 to R2. Median age 5 years (IQR: 3-11), 83% B-ALL, 12% T-ALL, 1% B-LBL and 4% T-ABL, 43% NCI high risk. Median follow-up for R1 is 76 months and R1 or R2 is 72 months. Overall, we found no difference in CNSR (HR: 0.99 (0.65-1.51), p=0.97, 5-year rates: 5.6% and 5.6%), or any other endpoints for R2IM. However, there was an interaction between the R1 and R2IM randomisations (p=0.006 for EFS) with inferior outcomes for patients treated with short dexamethasone followed by HDM, particularly in those who did not receive pulses (Figure 1). Limiting analyses to patients treated with standard dexamethasone (N=995, including those that received it after closure of R1) there was a significant reduction in BMR rate with HDM (HR 0.62 (95% CI: 0.40 - 0.95) p = 0.029) and a trend for improvements in EFS and OS (HRs: 0.75 (95%CI: 0.53 – 1.04), p=0.087 and 0.61 (0.37 – 1.03), p=0.067) but no difference in CNSR. In subgroup analyses there were no significant interactions, but the effect appeared stronger for B-lineage, NCI high risk and MRD low risk patients (Figure 2). Overall, the BMR for R2pulses was non-inferior (+2.1% increase BMR at 5 years for ALL patients (95% CI: -1.4% to 4.7%), HR 1.22 (95%CI: 0.89 – 1.67). Considering all four R2 treatment arms in standard dexamethasone only, standard IM without pulses has a lower EFS, whilst there is no appreciable benefit of pulses in HDM treated patients; 5-year EFS difference: -2.8% (95% CI: -7.4% to 4.4%) and BMR (ALL): +0.4% (-6.7% to 4.3%).ConclusionsHDM does not improve CNSR within a UKALL treatment backbone, but pre-specified analyses suggest it may improve BMR for some sub-groups of B-lineage patients when given following standard dexamethasone induction. Although the ‘no pulses’ arm was non-inferior overall for BMR, further sub-group and toxicity analyses are to be performed and will presented at the meeting.AcknowledgementsChildren with Cancer, Blood Cancer (grant ref 09042) and Cancer Research UK funded the trial.Disclosures: Kirkwood: Kite: Consultancy, Honoraria. Rowntree: Pfizer: Membership on an entity's Board of Directors or advisory committees; Lilly: Membership on an entity's Board of Directors or advisory committees; KITE pharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.PRESS RELEASE 2022:High-dose methotrexate may make post-treatment steroids unnecessary for some children with ALL or LBL214: High Dose Methotrexate Does Not Reduce the Risk of CNS Relapse in Children and Young Adults with Acute Lymphoblastic Leukaemia and Lymphoblastic Lymphoma. Results of the Randomised Phase III Study UKALL 2011The results of a new study answer some questions and raise new ones about the optimal treatment strategy for children and young adults living with acute lymphoblastic leukemia (ALL) or lymphoblastic leukemia (LBL). The randomized study is the first to test whether the use of a shorter, higher-dose course of dexamethasone (a steroid) during the first phase of cancer treatment is associated with reduced toxicity. It also analyzed the effects of using a higher dose of the chemotherapy drug methotrexate and of omitting pulses of dexamethasone along with the chemotherapy drug vincristine monthly following initial treatment. Monthly pulses of vincristine and dexamethasone are commonly used as a “maintenance” strategy to help prevent cancer from coming back in the first few years following treatment.The findings indicate that an initial course of daily higher dose dexamethasone (10mg/m2) spanning two weeks did not reduce toxicity compared to the standard regimen (6 mg/m2), which lasts four weeks. The results also indicate that, when given with the standard dexamethasone regimen, high-dose methotrexate reduces the risk of bone marrow but not central nervous system relapse for some sub-groups of ALL and that pulses of dexamethasone and vincristine may not have added benefit in patients who have received high dose methotrexate.“Based on our results, if you give high-dose methotrexate after standard dexamethasone in the induction phase, omission of pulses may not reduce the chance of cure, although that conclusion should be considered tentative given the confounding interactions,” said Ajay Vora, MD, of the Great Ormond Street Hospital for Children in London.According to initial study findings, pulses were associated with an increased risk of behavior change, muscle weakness, and high blood sugar; the researchers are currently analyzing the data further to assess the effect of the pulses on quality of life.The trial had two main phases and examined three main questions. For the first phase, researchers randomized 1,902 patients to receive either a two-week higher-dose course or a four-week course of dexamethasone during initial treatment. The results for that phase, reported in 2017, indicated the short course of steroids brought no reduction in toxicity and may be slightly less effective.For the second phase, researchers randomized 1,570 patients to four groups: high-dose methotrexate plus dexamethasone and vincristine pulses, high-dose methotrexate without pulses, standard-dose methotrexate with pulses, and standard-dose methotrexate without pulses. Some patients were enrolled in both phases of the trial while others only participated in one phase or the other.Key endpoints for the second phase focused on whether the steroid pulses could be safely omitted without affecting bone marrow relapse or five-year event-free survival and whether the high-dose methotrexate could improve rates of relapse in the central nervous system. For high dose methotrexate, the results showed no significant differences overall for most endpoints. Researchers did find a significant interaction with the dexamethasone regimen given in the first phase, with patients treated with the four- week schedule showing improvements in bone marrow relapse rates when treated with high dose methotrexate. Overall, the results suggested that steroid pulses could be safely omitted without adversely affecting bone marrow relapse. However, omitting the pulses was associated with a decrease in event- free-survival overall. This effect was smaller in those treated with four-week dexamethasone and high dose methotrexate, suggesting it may be possible to omit pulses with this treatment schedule.2“We found that the interactions are highly significant, which is something nobody expected,” said Dr. Vora. “In addition, we were surprised that high-dose methotrexate seems to bring a benefit with respect to relapses primarily in the bone marrow and not the central nervous system, and we don’t have a biologically plausible explanation for that finding.”Going forward, researchers will be analyzing quality of life outcomes related to the dexamethasone- vincristine pulses for further insights into the possible benefits of skipping this added therapy. They will also study outcomes at longer follow-ups to ensure these results hold. In addition, they noted that other studies are underway to further illuminate optimal treatment strategies for different patient subgroups.Amy Kirkwood, University College London, will present this study during an oral presentation on Saturday, December 10, 2022, at 2:45 p.m. Central time in room 265-268.
Interview with Matthias Stelljes MD, Head of the Allogeneic Stem Cell Program at the University of Münster, Germany
NEW ORLEANS, USA—For your patients with acute myeloid leukemia (AML) the benefit of prompt allogeneic hematopoietic cell transplantation (alloHCT) extends to those whose disease has relapsed or is refractory to induction therapy, and should not be delayed in favor of further intensive chemotherapy in an attempt to achieve a complete remission. That’s according to conclusions from the randomized phase three ASAP (As Soon As Possible) Trial, reported by German researchers at the American Society of Hematology (ASH) 2022 Annual Meeting.
https://ashpublications.org/blood/article/140/Supplement%201/9/488703/In-Patients-with-Relapsed-Refractory-AML
“Allogeneic stem cell transplantation is a very potent strategy which is curative for many patients,” said senior author of the study, Johannes Schetelig, Prof. Dr. med., at the University of Dresden in Germany. “Our study suggests that the international standard of bringing patients into remission first should be questioned, as it proves that allotransplant should be considered a standard treatment option even for patients with active disease.”
The new study was the first prospective randomized trial to assess whether or not high-dose “salvage chemotherapy” (to attempt to bring about a complete remission) made a difference in long-term outcomes after a stem cell transplant. Patients whose AML had relapsed or who did not respond to initial chemotherapy had similar outcomes when they proceeded directly to alloHCT compared with those who underwent intensive chemotherapy in the attempt to achieve complete remission first.
Retrospective data had established that having a complete remission prior to allogeneic hematopoietic cell transplantation was indeed a favorable risk factor for patients with AML. But the ASAP Trial had been the first to examine this relationship prospectively, the researchers noted.
“We were astonished. We never expected these results,” Schetelig said. “Patients did not gain additional benefit from salvage chemotherapy at all. It suggests we should think about starting the process of allotransplantation as soon as possible.”
In previous phase two trials the researchers had found transplanting patients who had active disease brought a benefit. “We had some good experience in the past where we were able to successfully treat patients with an allogeneic stem cell transplantation even in the setting of active disease,” said first author of the ASAP study, Matthias Stelljes MD, Head of the Allogeneic Stem Cell Program at the University of Münster, Germany.
Stelljes acknowledged that the majority of centers did not usually perform alloHCT in patients with relapsed or refractory AML with active disease. The new findings from ASAP, however, ran counter to the common practice of offering prompt transplantation only to patients who were in complete remission and clearly imply that many patients could skip the additional step of having salvage chemotherapy before receiving a transplant.
The study enrolled 281 patients treated for relapsed or refractory AML in Germany. Half of them were randomized to proceed directly to alloHCT and remaining half had salvage chemotherapy first. The median time from randomization to transplant was four weeks among those proceeding directly to a transplant and eight weeks among those receiving salvage chemotherapy first. Researchers tracked outcomes for a median of just over three years.
In the standard arm patients had salvage therapy with high dose cytarabine(ara-C) and mitoxantrone and then received an allogeneic transplant. This was either in subsequent remission or with active disease in those in whom no remission could be achieved, Stelljes told the Audio Journal of Oncology. “In the experimental arm we did not perform any salvage treatment. We just tried to get the patient as soon as possible to transplant. We were able to get most of the patients, without additional therapy, to allo transplant within three to four weeks,” he said.
The two study groups showed similar outcomes in all key endpoints. The primary endpoint of complete remission 56 days after transplant was achieved in 84.1 percent of patients in the direct-to-transplant arm and 81.3 percent of patients in the salvage chemotherapy arm. The groups also had similar rates of overall survival at one year (around 70 per cent). Just over half of them were alive three years after randomization.
In the experimental arm, patients were followed under a policy of “watchful waiting” which permitted some treatment while the search for a transplant donor was in progress, but not at doses aimed at achieving complete remission. Three quarters of them had transplants before any such treatment was needed, Stelljes noted.
Since transplantation could only take place if a donor was available, the search for a donor began at primary diagnosis, Stelljes said, and not at the time of relapse of refractory disease.
He highlighted the role of clonal selection of resistant cancer cells that can arise from the exposure patients have to cancer drugs. Prompt transplantation reduces the time during which patients are exposed to chemotherapy and should increase the success rate of transplantation in achieving long remissions, he noted. “The main message is: Contact your transplant center as soon as possible, and stay in contact with the transplant center.”
NOTES:Study favors immediate progression to stem cell transplant for hard-to-treat AML even without achieving complete remission firstABSTRACT 4, American Society of Hematology 2022 Annual Meeting, New Orleans, USA.TITLE:In Patients with Relapsed/Refractory AML Sequential Conditioning and Immediate Allogeneic Stem Cell Transplantation (allo-HCT) Results in Similar Overall and Leukemia-Free Survival Compared to Intensive Remission Induction Chemotherapy Followed By Allo-HCT: Results from the Randomized Phase III ASAP TrialABSTRACT 4 ASH 2022:In Patients with Relapsed/Refractory AML Sequential Conditioning and Immediate Allogeneic Stem Cell Transplantation (allo-HCT) Results in Similar Overall and Leukemia-Free Survival Compared to Intensive Remission Induction Chemotherapy Followed By Allo-HCT: Results from the Randomized Phase III ASAP TrialProgram: General SessionsSession: Plenary Scientific SessionHematology Disease Topics & Pathways:MDS, clinical trials, AML, adult, Acute Myeloid Malignancies, Research, Clinical Research, Chronic Myeloid Malignancies, Diseases, therapy sequence, Therapies, Myeloid Malignancies, Human, Study PopulationSunday, December 11, 2022, 2:00 PM-4:00 PMMatthias Stelljes, Prof. Dr. med.1, Jan Moritz Middeke, MD2, Gesine Bug, MD3, Eva-Maria Wagner, MD4, Lutz Peter Mueller, MD5, Schmid Christoph6, Stefan W. Krause, MD7, Wolfgang Bethge, MD8, Edgar Jost9, Uwe Platzbecker, MD10, Stefan Klein, MD11, Jörg Schubert12, Judith Niederland13, Martin Kaufmann, MD14, Kerstin Schäfer-Eckart15, Markus Schaich, MD16, Henning Baldauf17, Friedrich Stölzel18, Cathleen Petzold, PhD17, Christoph Röllig, MD, MSC19, Nael Alakel, MD20, Björn Steffen, MD21, Beate Hauptrock22, Christian Reicherts, MD23, Christoph Schliemann, MD24, Hubert Serve, MD21, Alexander H. Schmidt, MD, PhD25, Martin Bornhäuser, MD26, Jan-Henrik Mikesch, PD, MD24 and Johannes Schetelig, MD, MSc17,201Department of Medicine / Hematology and Oncology, University of Muenster, Muenster, Germany2Department of Internal Medicine I, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany3Department of Medicine II, Hematology and Oncology, University Hospital Frankfurt, Frankfurt, Germany4Haematology and Oncology, University Medical Center, University Medicine Mainz, Mainz, Germany5University Hospital, Martin-Luther-University Halle-Wittenberg, Halle, Germany, Halle (Saale), Germany6Augsburg University Hospital and Medical Faculty, Augsburg, Germany, Augsburg, Germany7University Hospital Erlangen, Germany, Erlangen, Germany8Department of Hematology, Oncology, Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany9University Hospital Aachen, Germany, Aachen, Germany10Department for Hematology, Cell Therapy and Hemostaseology, University of Leipzig Medical Center, Leipzig, Germany11Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany12Elblandklinikum, Riesa, Germany, Riesa, Germany13Helios Klinikum Berlin-Buch, Berlin, Germany, Berlin-Buch, Germany14Medical Centre, Robert-Bosch-Hospital,, Stuttgart, Germany15Department of Internal Medicine V, Nuremberg Hospital North, Paracelsus Medical University, Nuremberg, Germany16Department of Hematology, Oncology and Palliative Care, Rems-Murr-Klinikum Winnenden, Germany, Winnenden, Germany17Clinical Trials Unit, DKMS gGmbH, Dresden, Germany18University Hospital, TU Dresden,Germany, Dresden, Germany19University Hospital, TU Dresden, Germany, Dresden, Germany20University Hospital TU Dresden, Germany, Dresden, Germany21Department of Hematology and Oncology, University Hospital Frankfurt am Main, Frankfurt am Main, Germany22University Hospital Mainz, Germany, Mainz, Germany23Department of Hematology, Oncolog and Pneumology, University of Münster, Muenster, Germany24Department of Hematology, Oncolog and Pneumology, University of Münster, Münster, Germany25DKMS gGmbH, Tubingen, Germany26Department of Medicine I, University Hospital Carl Gustav Carus Dresden, Dresden, GermanyIntroduction:For patients (pts) with AML, a complete remission (CR) prior to allogeneic hematopoietic cell transplantation (alloHCT) is a favourable risk factor. However, whether pts with relapsed or refractory (r/r) AML benefit from an attempt to induce CR with intensive chemotherapy (CT) prior to alloHCT is unknown. Sequential conditioning within 12 days prior to alloHCT with high-dose cytarabine or melphalan followed by reduced intensity conditioning leads to good results as well. Therefore, we asked whether intensive remission induction CT prior to alloHCT really improves outcome compared to immediate alloHCT after sequential conditioning without attempt to induce a CR before transplantation.Methods:Adult pts with poor responsive non-favourable AML after first induction therapy (IT-1) or AML relapse, eligible for intensive CT and alloHCT, with either a matched sibling donor (MSD), an HLA-compatible (≥9/10) unrelated donor (UD) or ongoing donor search with two potential UD with ≥90% HLA-matching probability were enrolled. Patients were randomized 1:1 to a remission induction strategy (RIST-arm) with 3 g/m2 cytarabine (1 g/m2 for pts >60 years) twice daily on days 1-3 plus 10 mg/m2 mitoxantrone on days 3-5 (HAM) and subsequent alloHCT (remission induction strategy, RIST-arm) or to disease control (DISC-arm) prior to sequential conditioning and alloHCT. In the DISC-arm watchful waiting (w&w) was recommended, but low-dose cytarabine (LDAC) and single doses of mitoxantrone were permitted for disease-control. The primary endpoint was treatment success, defined as CR@day56 after alloHCT. Statistically, the goal was to show non-inferiority (NIF) for the DISC-arm with a NIF-margin of 5% and a one-sided alpha of 2.5%. Major secondary endpoints were overall survival from randomization and leukemia-free survival from CR@day56.Results:A total number of 281 pts (183 pts with poor response after IT-1 and 98 pts after relapse) were enrolled. The full analysis set comprised 276 pts after exclusion of five pts due to violation of inclusion criteria. Median age was 61 years (interquartile range [IQR] 52-66 years) and the HCT-CI was ≥3 in 37.3% of pts. At randomization, 39 pts had MSD, 133 pts had an HLA-compatible UD with confirmed HLA-typing, and 104 pts had ongoing UD searches. 272 pts were treated per protocol, 138 pts in the DISC- and 134 in the RIST-arm.In the DISC-arm 105 of 138 pts (76%) were kept on w&w until start of sequential conditioning, while 33 pts (24%) needed disease-control measures. In the RIST-arm all pts received HAM. Sixty-two out of 134 pts (46%) achieved a CR. Five pts received a second course of intensive CT. The remaining pts proceeded to alloHCT without further attempts to induce a CR. The median time to alloHCT was 4 weeks in the DISC-arm and 8 weeks in the RIST arm. At 24 weeks from randomization 98% and 96% of pts had been transplanted in the DISC and RIST arm, respectively. Figure 1 A shows incidences of alloHCT and CR achievement in both arms. The primary endpoint CR@day56 after alloHCT was reached by 84.1% of pts in the DISC-arm and 81.3% of pts in the RIST-arm (test for non-inferiority, p=0.047). One-year leukemia-free survival from CR@day56 was 71.5% in the DISC-arm and 69.9% in the RIST-arm (z test, p=0.8).The median follow-up from randomization is 37 months. According to the intention-to-treat, 1-year and 3-years overall survival from randomization was 69.1% (95%-CI, 60.6-76.1%) versus 71.9% (95%-CI, 63.3-78.9%) and 51.0% (95%-CI, 41.8-59.6%) versus 54.2% (95%-CI, 44.4-62.9%) in the DISC- versus RIST-arm, respectively (log-rank p=0.47) (Figure 1B).Conclusions:This is the first randomized controlled trial, which questioned the benefit of intensive remission induction CT prior to alloHCT for pts with r/r AML. Chemotherapy with high-dose cytarabine and mitoxantrone before alloHCT did not result in a higher overall success rate and did not confer a survival advantage. Watchful waiting followed by sequential conditioning and alloHCT resulted in comparable overall CR rates and survival. These data support sequential conditioning and alloHCT without prior remission induction CT whenever a stem cell donor is readily available. Finally, these results underline the importance of facilitating alloHCT as most effective anti-leukemic therapy in patients with r/r AML and stress the need for starting donor search at diagnosis.
Ibrutinib Enables Transplant-Free Therapy for Mantle Cell Lymphoma
NEW ORLEANS, USA—Many patients eligible for autologous stem cell transplantation for their mantle cell lymphoma (under current best practice recommendations) could be treated as effectively—and potentially with less toxicity—with the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, according to findings from Munich, Germany.
The Randomized Triangle Trial, conducted by the European Mantle Cell Lymphoma Network, reported positive findings about a transplant-free approach to the American Society of Hematology 2022 Annual Meeting.
https://ashpublications.org/blood/article/140/Supplement%201/1/490022/Efficacy-and-Safety-of-Ibrutinib-Combined-with
Audio Journal of Oncology correspondent Peter Goodwin talked with study leader Martin Dreyling MD PhD, Professor of Medicine at LMU (Ludwig Maximilian University) Hospital in Munich, Germany about their findings that strongly suggest standard chemotherapy plus ibrutinib (with or without autologous stem cell transplantation) should be the new first-line standard of care for patients with mantle cell lymphoma.
Toxicity
But the German team also noted that the high efficacy of chemotherapy brought high toxicity rates. So, they compared the standard induction (with a cytarabine-containing regimen plus autologous transplant and rituximab maintenance) with two experimental arms, said Dreyling. “One was a simple add-on design—which means ibrutinib [was] added to [standard] induction and maintenance. And the third arm was even more interesting: substituting for autologous transplant.”
“The add-on design resulted in a significant improvement of progression free survival—around 15 per cent after three years: in my opinion highly clinically relevant,” he said. Also, the study found that a group of difficult-to-treat patients—those whose tumors had p53 gene alterations—had specifically benefited from the addition of ibrutinib.
Patients who took the targeted drug ibrutinib had rates of failure-free survival (FFS) and overall survival (OS) that were similar to the current standard of care—whether or not they received a stem cell transplant in addition to ibrutinib. Those treated with ibrutinib who did not have ASCT had significantly lower rates of toxicity. And in the arm in which ibrutinib was added to transplantation, the toxicity was no higher than among patients treated with standard of care, the study found.
“We are moving away from intensive chemotherapy to [a] targeted approach. The new standard of care in younger patients is still a combination of chemo plus ibrutinib. The future, I hope, will be skipping chemotherapy [altogether] and moving to a purely targeted approach—hopefully leading to better outcomes, but definitely better tolerability of our treatment regimens,” Dreyling told OT.
Study details
The trial enrolled 870 adult patients up to 65 (median age 57 years) treated for MCL in 13 European countries and Israel. All patients were eligible for ASCT. 288 of them (group A) were assigned to receive standard care (high-dose cytarabine-containing immunochemotherapy followed by ASCT and rituximab maintenance). 292 patients (group A + I) were treated with the same standard care plus ibrutinib, and 290 patients received ibrutinib without having a transplant (group I).
Transplant not superior
After a median follow-up of 31 months, group A failed to show superiority over group I in terms of FFS (three-year FFS was 72 per cent compared with 86 per cent in group I (p=0.9979, hazard ratio: 1.77). In group A+I, the FFS was superior to group A: 88 per cent compared with 72 per cent in group A (p=0.0008, hazard ratio: 0.52). OS was 86 per cent in group A, 91 per cent in group A+I, and 92 per cent in group I.
Toxicities
The study found no substantial differences in the incidence of grade three to five adverse events (AEs) during induction with R-CHOP/R-DHAP versus ibrutinib-R-CHOP/R-DHAP.
But during maintenance therapy there were substantially more grade three to five AEs in group A+I as compared either to group A or to group I. Neutropenia, leukopenia, febrile neutropenia, infections and cardiac disorders were all increased—many doubled in incidence—suggesting that ibrutinib may be best used as a replacement for stem cell transplantation rather than an addition.
“We have to wait for the full results,” said Dreyling. “So far, we don’t see any difference between [the] two ibrutinib curves for progression-free survival and overall survival. But already both curves are numerically superior to the old standard, autologous transplant only. I think clinicians will interpret these results as suggesting you may essentially substitute autologous transplant with ibrutinib to avoid its well-known long-term toxicities,” he said.
“From the perspective of toxicity, the ideal regimen is a combination of conventional chemotherapy plus ibrutinib,” said Dreyling.
His reasoning for reaching this conclusion was that not only had failure free survival improved when ibrutinib had been added to standard transplant therapy but the removal of transplantation altogether had proved highly beneficial.
Avoiding transplantation
The head-to-head comparison of ibrutinib versus ASCT had been even more interesting, he said, because skipping autologous transplant significantly reduced toxicity—which is what the study found. “When we started, we said autologous transplant had to be superior to remain the standard of care. However, to our surprise, what we observed was a flip-around of the curve. In fact, the ibrutinib arm was superior to autologous transplant.”
Overall survival
Although the statistical analysis had not yet be completed, both of the ibrutinib-containing arms of the study resulted in numerically superior overall survival. “That somewhat confirms that the life cycle of autologous transplant—in my opinion—is over and we now move on to the targeted approaches,” said Dreyling.
There was a big gain to be made for patients by skipping the acute toxicity of transplantation, Dreyling said. This was in the range of 60 per cent incidence of grade three to five myelosuppression and a 20 per cent infection rate caused by it. “This is totally skipped in the ibrutinib-only arm,” he said.
Quality of life
Dreyling said that from the doctor’s perspective ASCT was easy, but was not at all easy from the patient’s perspective. “We have a lot of patients with delayed reduction of general quality of life. And therefore, I think this is really an important step forward—besides all the late toxicities of autologous transplant we couldn’t yet analyze so far,” he said.
Dreyling pointed out emphatically that the study had been led and funded by academic institutions which he said was hugely important. “This study proves the role of academic trials—independently performed,” he said. Recruiting almost 900 patients with mantle cell lymphoma—also proved the value of international collaboration, he said.
ASH 2022 Annual MeetingABSTRACT 1: Efficacy and Safety of Ibrutinib Combined with Standard First-Line Treatment or As Substitute for Autologous Stem Cell Transplantation in Younger Patients with Mantle Cell Lymphoma: Results from the Randomized Triangle Trial By the European MCL NetworkProgram: General SessionsSession: Plenary Scientific SessionHematology Disease Topics & Pathways:Research, clinical trials, adult, Lymphomas, non-Hodgkin lymphoma, Non-Biological therapies, Clinical Research, B Cell lymphoma, Chemotherapy, Diseases, aggressive lymphoma, Therapies, Lymphoid Malignancies, young adult , Study Population, HumanSunday, December 11, 2022, 2:00 PM-4:00 PMMartin Dreyling, MD1, Jeanette K. Doorduijn, MD, PhD2, Eva Gine, MD, PhD3, Mats Jerkeman, MD, PhD4, Jan Walewski, MD5, Martin Hutchings, MD, PhD6, Ulrich Mey, MD7,8, Jon Riise, MD, PhD9, Marek Trneny, MD10, Vibeke K.J. Vergote11, Melania Celli12, Ofer Shpilberg, MD, MPH13, Maria Gomes da Silva14, Sirpa Leppa, MD, PhD15, Linmiao Jiang16, Christiane Pott17, Wolfram Klapper, MD18, Döndü Gözel1, Christian Schmidt, MD1, Michael Unterhalt, MD, PhD1, Marco Ladetto, MD19 and Eva Hoster1,20*
1Department of Internal Medicine III, LMU University Hospital Munich, Munich, Germany2Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands3Department of Hematology, Hospital Clinic of Barcelona, IDIBAPS, CIBERONC, GELTAMO, Barcelona, Spain4Division of Oncology, Skane University Hospital and Lund University, Lund, Sweden5Department of Lymphoid Malignancies, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland6Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark7Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland8Oncology and Hematology, Kantonsspital Graubünden, Chur, Switzerland9Department of Oncology, Oslo University Hospital, Oslo, Norway10First Department of Internal Medicine - Hematology, General University Hospital and First Faculty of Medicine, Charles University, Prague, Czech Republic11Department of Hematology, University Hospitals Leuven, Leuven, Belgium12U.O. di Ematologia, Ospedale degli Infermi di Rimini, Rimini, Italy13Institute of Hematology, Assuta Medical Centers, Tel-Aviv, Israel14Department of Hematology, Instituto Português de Oncologia de Lisboa, Lisbon, Portugal15Department of Oncology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland16Institute for Medical Information Processing, Biometry and Epidemiology (IBE), LMU University Munich, Munich, Germany17Clinic for Internal Medicine II - Haematology, Oncology, University Clinic Schleswig-Holstein, Kiel, Germany18Department of Pathology, Hematopathology Section and Lymph Node Registry, Universitätsklinikum Schleswig-Holstein, Kiel, Germany19Department of Translational Medicine, University of Eastern Piedmont and Az Ospedaliera Santi Antonio e Biagio e Cesare Arrigo, Alessandria, Italy20Institute for Medical Information Processing, Biometry and Epidemiology, LMU Munich, Munich, Germany
On behalf of the European MCL NetworkML and EH contributed equallyIntroduction: High-dose cytarabine-containing immunochemotherapy followed by autologous stem cell transplantation (ASCT) and rituximab maintenance represents the current standard of care for younger mantle cell lymphoma (MCL) patients. The BTK-inhibitor ibrutinib has shown promising efficacy in relapsed (Dreyling et al, Hemasphere 2022) and previously untreated older MCL patients (Wang et al., NEJM 2022). In 2016, the European MCL Network initiated the randomized, open-label, 3-arm TRIANGLE trial to evaluate the addition of ibrutinib to standard treatment (arm A+I) in comparison to the previous standard treatment (arm A) and an ibrutinib containing treatment without ASCT (arm I).Patients and methods: Patients with previously untreated, advanced stage II-IV MCL, up to 65 years and suitable for high-dose cytarabine and ASCT were randomized 1:1:1 to the 3 trial arms A, A+I, and I in 13 European countries and Israel. Study treatment consisted of 3 cycles R-CHOP/R-DHAP without (arm A) or with ibrutinib added to R-CHOP cycles and 2 years maintenance (arms A+I, I). ASCT was planned for responding patients of arms A and A+I. Rituximab maintenance could be applied according to national guidelines in all responding patients irrespective of the trial arm. For the primary outcome, failure-free survival (FFS), stable disease at the end of induction, any progression, or death were counted as events. Three pairwise log-rank tests for FFS were monitored with regular pre-planned interim analyses maintaining each a one-sided 0.0167 significance level. A pre-defined decision criterion based on the statistical significance of the treatment comparisons was established to determine the future treatment recommendation. Secondary outcomes were overall response (OR), complete remission (CR), overall survival (OS), and grade 3-5 AEs.Results: Between July 2016 and December 2020, 870 patients were randomized to A (n=288), A+I (n=292), and I (n=290). Median age was 57 years (range 27-68), 76% of the patients were male, 87% had stage IV, and 58%/27%/15% had low/intermediate/high risk MIPI. OR and CR rates were 94% and 36% of 272 evaluable patients in arm A (R-CHOP/R-DHAP) as compared to 98% and 45% of 559 evaluable patients in the combined A+I/I arms (ibrutinib-R-CHOP/R-DHAP). After a median follow-up of 31 months, A failed to show superiority over I in terms of FFS with 3-year FFS 72% (A) vs. 86% (I; p=0.9979, hazard ratio: 1.77, Figure 1A). A+I was superior to A in terms of FFS with 3-year FFS 88% (A+I) vs. 72% (A; p=0.0008, hazard ratio: 0.52). Subgroup analyses by the intention to apply rituximab maintenance did not change the main results on the lack of superiority of A vs. I and the superiority of A+I vs. A . Statistical monitoring for the FFS comparison of A+I vs. I is still ongoing. Three-year OS was 86% in A, 91% in A+I, and 92% in I (Figure 1B). There were no substantial differences in the occurrence of grade 3-5 AEs during induction with R-CHOP/R-DHAP vs ibrutinib-R-CHOP/R-DHAP (neutropenia: 47%/49% of patients, leukopenia: 15%/15%, febrile neutropenia: 9%/12%, infections and infestations: 9%/12%, cardiac disorders: 2%/3%). The two ASCT-containing arms did not substantially differ in grade 3-5 AEs (A/A+I: neutropenia: 36%/33%, febrile neutropenia: 20%/22%, leukopenia: 17%/17%, infections and infestations: 17%/20%). In contrast, during maintenance, there were substantially more grade 3-5 AEs in A+I as compared to A and I (A+I/A/I: neutropenia: 44%/17%/23%, leukopenia: 4%/2%/2%, febrile neutropenia: 6%/3%/3%, infections and infestations: 25%/13%/19%, cardiac disorders: 3%/1%/4%).Conclusions: The addition of ibrutinib during induction and as maintenance with or without ASCT showed strong efficacy with acceptable toxicity. It has been clearly demonstrated that the current standard high-dose regimen is not superior to the new ibrutinib-containing regimen without ASCT. More follow-up is needed to clarify the role of ASCT in the context of ibrutinib-containing treatment. However, the current results already support the use of ibrutinib in the first-line treatment of younger MCL patients.
January 10, 2023
Fast Durable Responses to Bi-Specific Antibody Therapy In Heavily Pre-Treated Multiple Myeloma
INTERVIEW WITH:Ajai Chari MD, Associate Professor of Medicine and Director of Clinical Research in the Multiple Myeloma Program at Mount Sinai School of Medicine in New York, USA.NEW ORLEANS, USA—The bispecific antibody talquetamab, classed as a “T-cell redirecting therapy” achieved high response rates in the phase one/two multi-national MonumenTAL-1 study investigating 288 patients who had heavily pre-treated refractory multiple myeloma.
Findings reported at the American Society of Hematology 2022 Annual Meeting showed that nearly three-quarters of patients treated had “complete” or “very good partial” responses within one or two months, and median response durations of around nine months.https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.8015
“Remarkably in this unmet need we saw response rates of 73 to 74 per cent. The responses were maintained in triple-class refractory patients, penta-drug refractory patients, ISS (International Staging System) three high-risk disease,” said Ajai Chari MD, Associate Professor of Medicine and Director of Clinical Research in the Multiple Myeloma Program at Mount Sinai School of Medicine in New York, USA.
“The median time to response was one month—which is outstanding. And the median time to “best response” was slightly over two months—which is great, because it means that these patients who had explosive disease (these are not CAR-T cherry-picked patients with really indolent progression) were benefiting in high percentages—and quickly, and deeply,” Chari told the Audio Journal of Oncology.
Although patients with extra-medullary disease had fared slightly less well, their responses had still been good, he said. “Even there, there was an impressive 50 per cent response rate.”
Talquetamab was an off-the-shelf bispecific antibody, that binds to both T cells and multiple myeloma cells, said Chari. This facilitates an immune response to destroy myeloma cells by bringing T cells to the cancer. Its twin targets were the CD3 T-cell receptors and the cancer cell surface receptor known as G protein-coupled receptor family C group 5 member D (GPRC5D).
“[Previously] we only had naked antibodies. And a bispecific antibody is different. Like with all antibodies it has the Y-shaped structure, but unlike typical antibodies it binds two different targets. One target is the T cell—with CD3; and the other target is GPRC5D, which is a novel target in myeloma. It’s over-expressed particularly on malignant plasma cells, less so on normal plasma cells, and—importantly—not on the hematopoietic stem cell compartment—Which we think is a favorable finding,” said Chari.
“You basically can engage the patient’s own T-cells to try to attack the myeloma. And it’s a little surprising how remarkable this whole approach has been: Because patients with myeloma who are entering these studies have typically five to six lines of therapy over six years, are usually in their late sixties [or] early seventies, and you wouldn’t think that their T-cells would even be robust, and fit, and present, enough to generate results—let alone the outstanding results we’re seeing,” he said.
In the MonumenTAL-1 study, patients with relapsed/refractory multiple myeloma, were treated with either of two recommended dosing regimens: 0.40 mg/kg of talquetamab subcutaneously at weekly intervals, or 0.80 mg/kg every other week.
Results
Patients in the weekly and bi-weekly dose regimens (equivalent in overall dose intensity) had similar outcomes in terms of response rates and toxicities. Nearly a third of patients had complete responses. More than half had “very good” partial responses. The responses deepened with time, and continued to a median of nine months duration. Median progression-free survival was 7.5 months.
The median time to a measurable response was approximately 1.2 months with either dosing regimen, and the median duration of response was 9.3 months in the patients treated with the weekly dosing.
“This means that three-quarters of these patients are looking at a new lease on life,” said Chari. “We’re hoping that this will soon become available so that patients can benefit.”
Side effects were relatively frequent, but mild in most patients. About three-quarters experienced cytokine release syndrome (immune activation—typically causing a fever). More than half of the study cohort had skin-related side effects such as rash. About a half reported dysgeusia (taste changes), and a similar proportion of study subjects had nail disorders. Only one in twenty patients discontinued talquetamab treatment early due to side effects.
Since response rates observed in the early-phase MonumenTAL-1 study had been, higher than with most currently accessible therapies, Chari suggested talquetamab could potentially be proven to be a viable option for patients with refractory multiple myeloma and offer the possibility of extending life.
Chari told the Audio Journal of Oncology he regarded bispecific antibodies as an alternative T-cell redirection strategy comparable to chimeric antigen receptor therapy (CAR-T)—that had achieved notable successes in hematologic malignancy in certain academic centers of excellence recently. But bi-specific antibodies could potentially be more universally available, because off-the-shelf agents could more easily be distributed to a wider range of patients—without the need to individualize the therapeutic agent in each case. “There’s every reason to hope that these could be brought to the community oncologist near you so you don’t have to keep going to these academic centers,” he said.
ASH 2022:157 Talquetamab, a G Protein-Coupled Receptor Family C Group 5 Member D x CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Phase 1/2 Results from MonumenTAL-1Clinically Relevant AbstractProgram: Oral and Poster AbstractsType: OralSession: 653. Myeloma and Plasma Cell Dyscrasias: Prospective Therapeutic Trials: Bispecific Monoclonal Antibodies in MyelomaHematology Disease Topics & Pathways:Biological therapies, Research, Clinical Research, Plasma Cell Disorders, Diseases, Therapies, Lymphoid MalignanciesSaturday, December 10, 2022: 12:00 PMAjai Chari1, Cyrille Touzeau2, Carolina Schinke3, Monique C. Minnema, MD, PhD4, Jesus Berdeja, MD5, Albert Oriol6, Niels WCJ Van De Donk, MD7, Paula Rodriguez Otero8, Elham Askari9, Maria-Victoria Mateos, MD10, Luciano J. Megala Costa, MD, PhD11, Jo Caers, PhD12, Leo Rasche, MD13, Amrita Y. Krishnan, MD, FACP14, Deeksha Vishwamitra15, Xuewen Ma15, Xiang Qin15, Katharine S. Gries, PhD, PharmD16, Michela Campagna17, Tara Masterson15, Brandi Hilder15, Jaszianne Tolbert15, Thomas Renaud18, Jenna D. Goldberg18, Christoph Heuck15, Jesús San-Miguel, MD, PhD19 and Philippe Moreau, MD20*1Mount Sinai School of Medicine, New York, NY2Centre Hospitalier Universitaire de Nantes, Nantes, France3Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR4University Medical Center Utrecht, Utrecht, Netherlands5Sarah Cannon Research Institute, Nashville, TN6Hospital Germans Trias I Pujol, Barcelona, Spain7Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands8University of Navarra, Pamplona, Spain9Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain10University Hospital of Salamanca/IBSAL/CIC, Salamanca, Spain11University of Alabama at Birmingham, Birmingham, AL12University of Liege, Liege, Belgium13University Hospital of Würzburg, Würzburg, Germany14City of Hope Comprehensive Cancer Center, Duarte, CA15Janssen Research & Development, Spring House, PA16Janssen Global Services, Raritan, NJ17Janssen-Cilag, Madrid, Spain18Janssen Research & Development, Raritan, NJ19Universidad de Navarra, Pamplona, Spain20University Hospital Hôtel-Dieu, Nantes, FranceIntroduction: G protein-coupled receptor family C group 5 member D (GPRC5D) has limited expression in normal human tissue but is highly expressed on malignant plasma cells, making it a promising immunotherapy target for patients (pts) with multiple myeloma (MM). Talquetamab is a first-in-class, off-the-shelf, T-cell redirecting bispecific antibody targeting both GPRC5D and CD3 receptors. MonumenTAL-1 is a phase 1/2 trial (NCT03399799/NCT04634552) of talquetamab in pts with RRMM. In phase 1 of MonumenTAL-1, collective safety, efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) data supported selection of 2 recommended phase 2 doses (RP2Ds) for talquetamab: 0.405 mg/kg subcutaneous (SC) weekly (QW) and 0.8 mg/kg SC every other week (Q2W). Here, we report results for pts treated at these RP2Ds in phase 1 and 2 of MonumenTAL-1.Methods: Eligible pts in phase 1 had measurable MM and had progressed on or were intolerant to standard therapies. Pts in phase 2 had received ≥3 prior lines of therapy (LOT), including ≥1 proteasome inhibitor, ≥1 immunomodulatory drug, and ≥1 anti-CD38 monoclonal antibody (ie, triple-class exposed). In phase 1, 0.405 mg/kg SC QW was a putative RP2D; this was modified to 0.4 mg/kg SC QW in phase 2 for convenience. Phase 1 and 2 data were combined for analysis. Step-up dosing was used to mitigate risk of severe cytokine release syndrome (CRS). Primary endpoint of phase 2 was overall response rate (ORR) per IMWG criteria based on independent committee review. Key secondary endpoints were duration of response (DOR), rate of very good partial response or better (≥VGPR), rate of complete response or better (≥CR), time to response, progression-free survival (PFS), and incidence of AEs. AEs were graded by CTCAE v4.03; CRS events were graded per ASTCT criteria. PD parameters were measured at baseline and through day 1 of cycle 2.Results: As of May 16, 2022, 288 pts with no prior exposure to T-cell redirecting therapies had received talquetamab at the RP2Ds in phase 1 or 2. In 143 pts treated at 0.4 mg/kg QW (median time since diagnosis: 6.7 years), median age was 67 years (range 46–86), pts received a median of 5 prior LOT (range 2–13), 31.1% had high-risk cytogenetics, 23% had extramedullary disease, 19.6% had ISS stage 3 disease, 100%/74% were triple-class exposed/refractory, and 73%/29% were penta-drug exposed/refractory; median follow-up was 11.0 months (range 0.5+–26.1). Baseline characteristics were similar among 145 pts who received 0.8 mg/kg Q2W (median follow-up: 5.1 months [range 0.2+–17.9]).In 143 pts treated at 0.4 mg/kg QW, ORR was 73% (≥VGPR: 58%; ≥CR: 29%). Responses were durable and deepened over time (Figure). Median time to response was 1.2 months (range 0.2–5.0). Median time to CR was 2.1 months (range 1.1–12.4). Median DOR was 9.3 months (95% CI, 6.6–20.2; range 1–23+). Median PFS was 7.5 months (95% CI, 5.7–9.2 [38% censored]). ORRs in pts who were triple-class refractory (72% [76/106]) and penta-drug refractory (71% [30/42]) were comparable to the overall population. Efficacy at 0.8 mg/kg Q2W will be presented at the meeting.The most common AEs at 0.4 mg/kg QW/0.8 mg/kg Q2W were CRS (79%/72%; grade 3: 2%/1%; grade 4: 0%/0%), dysgeusia (48%/46%; grade 3/4: not applicable [NA]), and anemia (45%/39%; grade 3: 31%/25%; grade 4: 0%/0%]); skin-related AEs occurred in 56%/68% (grade 3: 0%/1%; grade 4: NA) and nail disorders in 52%/43% (grade 3: 0%/0%; grade 4: NA) of patients. Cytopenias, including neutropenia in 34%/28% (grade 3: 20%/17%; grade 4: 10%/6%) and thrombocytopenia in 27%/27% (grade 3: 10%/8%; grade 4: 10%/8%), were generally limited to the first few cycles. At 0.4 mg/kg QW/0.8 mg/kg Q2W, infections occurred in 57%/50% of pts (grade ≥3: 19%/13%); 4.9%/6.2% discontinued, 8.4%/13.8% had dose delays, and 14.7%/6.2% had dose reductions due to AEs. There were 2 deaths due to COVID-19 (1 patient at each RP2D).Talquetamab exposure was comparable at the two RP2Ds. No clinically significant effect of anti-talquetamab antibodies on PK, efficacy, or AEs was observed.PD changes were comparable at both RP2Ds and consistent with talquetamab activity, including T-cell activation, redistribution, and induction of cytokines.Conclusions: Talquetamab demonstrated robust efficacy and manageable safety in pts with heavily pretreated RRMM. Additional phase 1 studies (NCT04586426; NCT04108195; NCT05050097) are evaluating talquetamab in combination with other agents in pts with RRMM.ASH 2022 PRESS BRIEF:Talquetamab Generates High Response Rate in Patients with Hard-to-treat Multiple Myeloma157: Talquetamab, a G Protein-Coupled Receptor Family C Group 5 Member D x CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Phase 1/2 Results from MonumenTAL-1In an early-phase trial, nearly three-quarters of patients who received talquetamab, a first-in-class experimental immunotherapy for multiple myeloma, saw a significant reduction in cancer burden within a few months. The study participants had all been previously treated with at least three different therapies without achieving lasting remission, suggesting talquetamab could offer new hope for patients with hard-to-treat multiple myeloma.“This means that three-quarters of these patients are looking at a new lease on life,” said Ajai Chari, MD, of The Tisch Cancer Institute at Mount Sinai in New York. “We’re hoping that this will soon become available so that patients can benefit.”Talquetamab binds to both T cells and multiple myeloma cells. This activates an immune response to destroy myeloma cells by bringing T cells to the cancer, a strategy that researchers described as “bringing your army to the enemy.” It also uses a different target than other approved therapies; in this case, the target is a receptor expressed on the surface of cancer cells known as GPRC5D.Multiple myeloma is a blood cancer that forms in plasma cells. Several treatments are available, but the prognosis can be very poor and many patients survive less than a year if the disease doesn’t respond to therapy or returns after several different treatments.The study enrolled a total of 288 patients who were unable to tolerate existing therapies or showed disease progression after at least three multiple myeloma therapies. After an initial phase generated encouraging results in terms of safety and efficacy, researchers began enrolling additional patients to assess the agent’s efficacy with two different dosing regimens—0.4 mg/kg weekly and 0.8 mg/kg every other week. Data from patients who had received these same dosing regimens in the first phase were included in the analysis for the second phase.Seventy-four percent of those receiving 0.4 mg/kg of talquetamab weekly and 73% of those receiving 0.8 mg/kg every other week saw a measurable improvement of their cancer following treatment, the primary endpoint for the trial’s second phase. More than 30% of patients in both groups had a complete response (no detection of myeloma-specific markers) or better and nearly 60% had a “very good partial response” or better (indicating the cancer was substantially reduced but not necessarily down to zero). The median time to a measurable response was approximately 1.2 months in both dosing groups and the median duration of response is 9.3 months to date with weekly dosing. Researchers are continuing to collect data on the duration of response in the group receiving 0.8 mg/kg every other week and for patients in both dosing groups who had a complete response or better.Side effects were relatively frequent, but typically mild. About three-quarters of patients experienced cytokine release syndrome (a sign of immune activation common with therapies that redirect T cells, typically causing a fever); 60% experienced skin-related side effects such as rash; about half reported taste changes; and about half reported nail disorders. Researchers said 5-6% of patients stopped talquetamab treatment early due to side effects.The response rate observed in this cohort, which Dr. Chari explained is higher than that of most currently accessible therapies, suggests talquetamab could offer a viable option for patients with hard-to-treat myeloma, offering a chance to extend patient lifespans.In a separate cohort, 51 patients who had previously received therapies that redirect T cells showed a response to talquetamab. In addition, several other studies are underway to assess the use of talquetamab in combination with other existing and investigational multiple myeloma therapies, which could allow patients to have similar or improved benefits, potentially in earlier stages of treatment.This study was funded by Janssen Research & Development LLC.Ajai Chari, The Tisch Cancer Institute at Mount Sinai, will present this study during an oral presentation on Saturday, December 10, 2022, at 12:00 noon in R02-R05.
An interview with: Byoung Chul Cho MD PhD, Thoracic Medical Oncologist, from the Yonsei Cancer Center at Yonsei University College of Medicine in Seoul, South Korea.
BARCELONA, Spain—A “next generation” ROS1 tyrosine kinase inhibitor (TKI), repotrectinib—studied in the phase one/two Trident-1 study among patients whose advanced non-small cell lung cancers (NSCLC) had tested positive for the ROS1 fusion protein receptor tyrosine kinase (encoded by the ROS1 oncogene)—resulted in high response rates with low toxicities, according to results reported at the 2022 European Organisation for Research and Treatment of Cancer-National Cancer Institute-American Association for Cancer Research (EORTC-NCI-AACR) Symposium on Molecular Targets and Cancer Therapeutics.
Byoung Chul Cho discusses the trial and its clinical implications for patients with ROS1 positive NSCLC (one or two per cent of all lung cancer cases).
Among the study patients treated at 150 hospitals around the world, some had never been treated with a ROS1 TKI, some had already been treated with one ROS1 TKI, some had been treated with a ROS1 TKI and platinum-based chemotherapy, and some had been treated with two different ROS TKIs. As of June 20, 2022, the primary efficacy population had included 71 TKI-naive patients and 56 TKI-pretreated patients with no prior chemotherapy.
“In TKI-naïve patients repotrectinib showed a 78 per cent objective response rate (tumor reduction of at least 30 per cent) and the 12 months duration of response was 86 per cent,” said Cho after his late breaking session at the Symposium. In the patients who had no prior chemotherapy who had been treated with a previous-generation ROS1 TKI he said they also found a good response rate. “Repotrectinib showed a 37 per cent objective response rate with a six months duration of response [of] 79 per cent,” he said.
A significant issue with ROS1 TKI treatment had been that patients usually developed the so-called G2032R resistance mutation that rendered further TKI therapy ineffective. “The G2032R resistance mutation is the most common resistance mechanism,” said Cho. “Repotrectinib showed objective response rate of 58 per cent in this population.”
Anti mTrk activity
Another putative advantage for the investigational agent in Trident-1 had been that it also inhibited mutated tropomyosin receptor kinase receptor (Trk: usually pronounced “track”) a molecular feature often found in association with ROS1. “So, in the Trident-1 trial we also evaluated the activity and safety of repotrectinib in m-Trk fusion-positive solid tumors in both TKI naïve and TKI pretreated populations,” Cho said. A phase one study by Besse and colleagues from Villejuif, France—working on Trident-1 in collaboration with Cho and others—had already found that repotrectinib demonstrated efficacy in TKI-naïve and TKI-pretreated patients and was generally well tolerated.
https://aacrjournals.org/mct/article/20/12_Supplement/P02-01/675917/Abstract-P02-01-Repotrectinib-in-patients-with
Brain metastases
When Cho was asked about the impact of the new TKI on cranial metastases he said the drug had been effective. “CNS metastasis is one of the commonest sites of metastasis after progression on a ROS1 TKI. In this study we [observed] a very high intracranial activity of repotrectinib in both TKI naïve and TKI pre-treated populations.” Nearly 90 per cent of the small number of patients with measurable tumors in the brain not previously treated with a ROS1 TKI had intracranial objective responses (iORR). Just less than half of those already treated with one prior ROS1—and half of those treated with one prior ROS1 TKI and chemotherapy—had iORR. But none of the patients pre-treated with both chemotherapy and a TKI had responded.
Cho said that repotrectinib had been generally well tolerated. “The most common side effects were low grade: grade one or two. The most common was low-grade dizziness. It occurred in about 60 per cent of patients,” he said. But despite this relatively high incidence of dizziness the incidence of treatment discontinuation had been low, he said—less than ten per cent.
“With around 16 months median follow up, the median duration of response to repotrectinib treatment in TKI naïve patients has not yet been met. This is very meaningful, and a clear measure to utilize repotrectinib in the TKI naïve setting,” said Cho. “The number two message is: We also demonstrated a high response rate in TKI-pre-treated ROS1 positive lung cancer. And we also demonstrated the activity of repotrectinib in G2032R mutant ROS1 positive lung cancer,” he said.
Strongest data
He regarded the data as the strongest yet seen with a TKI in this setting. “In our study we demonstrated the potential role and value of repotrectinib in both TKI naïve and TKI pretreated ROS1 positive advanced stage NSCLC,” he said.
For many patients with the ROS1 marker, Cho predicted an important role for repotrectinib in picking up the baton to take over from previous generation TKI therapy. “Because the current standard of care at the time of diagnosis of advanced stage ROS1 positive lung cancer is a ROS1 TKI such as crizotinib, or entractinib, so: After 15 or 20 month of progression-free survival the majority of patients experience disease progression due to acquired resistance. So, in the second line setting we [currently] only have cytotoxic chemotherapy. So, these data support the use of repotrectinib in the setting of resistance to prior ROS1 TKI in the first-line setting,” Cho said.
“Our data suggest that repotrectinib could represent a potential new treatment option for patients with ROS1 positive NSCLC in both TKI naïve and TKI pre-treated populations,” he concluded.
230106 Byoung clip project PRODUCTION MASTER 720P230106 Byoung clip project PRODUCTION MASTER 720P
Abstract P02-01: Repotrectinib in patients with NTRKfusion-positive advanced solid tumors: update from the registrational phase 2 TRIDENT-1 trial
Benjamin Besse; Christina Baik; Christoph Springfeld; Alice Hervieu; Victor Moreno; Lyudmila Bazhenova; Jessica J. Lin; D. Ross Camidge; Benjamin Solomon; Vamsidhar Velcheti; Anthonie J. van der Wekken; Enriqueta Felip; Dipesh Uprety; Denise Trone; Shanna Stopatschinskaja; Byoung Chul Cho; Alexander Drilon
ABSTRACT:
Background:
NTRK fusions drive a broad range of solid tumors. Two FDA approved TRK tyrosine kinase inhibitors (TKIs) have demonstrated efficacy in patients (pts) with NTRK fusion+ advanced solid tumors; however, emergent TRK solvent front (SF) and gatekeeper resistance mutations occur. Repotrectinib is a next-generation ROS1/TRK TKI with potency against wildtype and mutant forms of ROS1 and TRK. In preclinical studies, repotrectinib was more potent than larotrectinib, entrectinib, and selitrectinib against wildtype TRK, SF and gatekeeper mutations. Early interim data from the Phase 1/2 TRIDENT-1 trial led to Fast Track designation by the FDA for repotrectinib in TRK TKI-pretreated pts. This abstract is an updated analysis of this population and the first presentation of repotrectinib activity in TRK TKI-naïve pts.
Methods:
Pts with NTRKfusion+ advanced solid tumors were enrolled into the ongoing registrational Phase 2 TRIDENT-1 trial (NCT03093116). Pts with no prior TRK TKIs were enrolled into Expansion Cohort 5 (EXP-5) and pts who received up to 2 lines of prior TRK TKIs were enrolled into EXP-6. Prior chemotherapy and/or immunotherapy were allowed in both cohorts. The primary endpoint is cORR by Blinded Independent Central Review using RECIST v1.1. Results: As of efficacy data cutoff date of 28 July 2021, 8 pts in EXP-5 and 19 pts in EXP-6 had at least 2 post-baseline scans and were evaluable for efficacy analysis. Median age was 63 y (range 33–80) in EXP-5 and 50 y (range 23–81) in EXP-6; median number of prior lines of chemo/immunotherapy was 1 (range 0–2) in EXP-5 and 1 (range 0–4) in EXP-6. In EXP-6, 79% (15/19) of pts received 1 prior TRK TKI. Confirmed responses were reported by physician assessment. In EXP-5, cORR was 63% (5 of 8 pts; 95% CI: 24–91%) with DOR from 1.9+ to 7.4+ months (mo). In EXP-6, cORR was 47% (9 of 19 pts; 95% CI: 24–71%) with DOR from 1.9+ to 15.1 mo. In 10 pts enrolled in EXP-6 with a SF mutation, the cORR was 60% (6 of 10 pts; 95% CI: 26–88%). Median duration of treatment was 6.3 mo (range 0.9–13.4+) in EXP-5 and 8.1 mo (range 1.1–20.8) in EXP-6. An updated safety analysis for Phase 1 and Phase 2 (n=243) based on a data cut-off date of 4 May 2021 was conducted. Repotrectinib was generally well tolerated. Treatment-emergent adverse events (TEAEs) observed in ≥20% of patients were dizziness (62%), dysgeusia (43%), constipation (33%), dyspnea (30%), paresthesia (28%), anemia (26%), and fatigue (26%). The majority (77%) of dizziness TEAEs were Grade 1 and 4% were Grade 3; none of the dizziness events led to treatment discontinuation. Dose modifications remained infrequent (24% of pts had a dose reduction and 10% of pts discontinued study drug due to a TEAE).
Conclusions:
Repotrectinib is a next-generation ROS1 and TRK inhibitor. In an ongoing registrational Phase 2 trial, repotrectinib demonstrated efficacy in TRK TKI-naïve and TKI-pretreated pts and was generally well tolerated. Enrollment in the multi-cohort Phase 2 trial is ongoing.
Citation Format:
Benjamin Besse, Christina Baik, Christoph Springfeld, Alice Hervieu, Victor Moreno, Lyudmila Bazhenova, Jessica J. Lin, D. Ross Camidge, Benjamin Solomon, Vamsidhar Velcheti, Anthonie J. van der Wekken, Enriqueta Felip, Dipesh Uprety, Denise Trone, Shanna Stopatschinskaja, Byoung Chul Cho, Alexander Drilon. Repotrectinib in patients with NTRKfusion-positive advanced solid tumors: update from the registrational phase 2 TRIDENT-1 trial [abstract].
In:
Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P02-01.
ARROS-1 Study Finds ROS1 Tyrosine Kinase Inhibitor Has Promise as a Tumor Agnostic Therapy
BARCELONA, Spain—Findings from a study of a new investigational therapy targeting the ROS-1 receptor tyrosine kinase—mutated in some cancers—were reported at the 2022 EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics conference held in Barcelona.
First author Medical Oncologist Alex Drilon MD, Chief of the Early Drug Development Service at Memorial Sloan-Kettering Cancer Center in New York, gave the Audio Journal of Oncology his take on the safety and preliminary clinical activity of NVL-520: described as a “highly selective ROS1 inhibitor” in patients with solid tumors—mainly non-small cell lung cancer (NSCLC).
Patients selected for the study had gene rearrangements in the ROS-1 receptor tyrosine kinase. The aim was to test whether targeting gene fusions which are molecular driver of cancer could be more valid than individualising therapy to tumors of a specific organ.
Text from symposium ABSTRACT 8:
TITLE: Safety and preliminary clinical activity of NVL-520, a highly selective ROS1 inhibitor, in patients with advanced ROS1 fusion-positive solid tumors
AUTHORS: A. Drilon1, B. Besse2, D.R. Camidge3, S.H.I. Ou4, S.M. Gadgeel5, M.L. Johnson6, A. Calles7, M.J. de Miguel8, A.I. Spira9, E. Felip10, G. Lopes11, A.J. van der Wekken12, Y.Y. Elamin13, J. Green14, Y. Sun15, J. Soglia16, V.W. Zhu14, J.J. Lin17
INSTITUTIONS: Memorial Sloan Kettering Cancer Center, Early Drug Development Service, New York, US, Institut Gustave Roussy, Cancer Medicine, Villejuif, France, University of Colorado Cancer Center- Anschutz Medical Campus, Thoracic Oncology, Aurora, USA, University of California Irvine Medical Center, Medicine, Orange, USA, Henry Ford Cancer Institute, Internal Medicine, Detroit, USA, Sarah Cannon Research Institute, Oncology, Nashville, USA, Hospital Universitario Gregorio Marañón, Medical Oncology, Madrid, Spain, START Madrid- HM CIOCC, Medical Oncology, Madrid, Spain, NEXT Oncology - Virginia Cancer Specialists, Thoracic and Phase I Program, Fairfax, USA, Hospital Vall d'Hebron, Oncology, Barcelona, USA, Sylvester Comprehensive Cancer Center- University of Miami Miller School of Medicine, Medical Oncology- Thoracic Medical Oncology, Miami, USA, University of Groningen and University Medical Centre Groningen, Pulmonary Oncology, Groningen, Netherlands, MD Anderson Cancer Center, Thoracic Head & Neck Medical Oncology, Houston, USA, Nuvalent Inc., Clinical Development, Cambridge, USA, Nuvalent Inc., Biology, Cambridge, USA, Nuvalent Inc., Translational Development, Cambridge, USA, Massachusetts General Hospital, Medicine, Boston, USA
BACKGROUND: Oncogenic ROS1 fusions drive various malignancies, including 1-3% of non-small cell lung cancers (NSCLC). Rationally designed ROS1 tyrosine kinase inhibitors (TKIs) that surpass the limitations of FDA/EMA-approved (crizotinib/entrectinib) or other investigational agents are a medical need. The novel ROS1 TKI NVL-520 is highly selective and designed to avoid the neurologic toxicities associated with ROS1 TKIs that concurrently inhibit TRK (entrectinib/repotrectinib/taletrectinib). Furthermore, NVL-520 is brain-penetrant and targets a diverse array of ROS1 fusions and recalcitrant resistance mutations, including the ROS1 G2032R solvent-front mutation.
MATERIALS AND METHODS: ARROS-1 (NCT05118789) is a global, tumor-agnostic, phase 1/2 trial of NVL-520. In the ongoing phase 1 dose escalation, patients are required to have a previously treated ROS1 fusion-positive solid tumor, including NSCLC treated with ≥1 prior ROS1 TKI. Primary objectives are to determine the recommended phase 2 dose (RP2D) and, if applicable, the maximum tolerated dose. Additional objectives include safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity. Response (RECIST v1.1) was investigator assessed. Data cut: June 13, 2022.
RESULTS: Twenty patients (19 NSCLC, 1 pancreatic cancer) have received NVL-520 orally at dose levels of 25-100 mg once daily. Patients received a median of 3 (range: 1-9) prior anticancer therapies, including any ROS1 TKI (100%); investigational ROS1 TKI (85%, including lorlatinib in 55%, repotrectinib in 40%); ≥2 ROS1 TKIs (75%); any chemotherapy (80%); ≥2 lines of chemotherapy (50%). At baseline, 55% had CNS metastases and 45% had ROS1 G2032R. No dose-limiting toxicities (DLTs), dose reductions, or drug-related treatment discontinuations have been reported. All treatment-related adverse events (TRAEs) were grade 1. The only TRAE in >1 patient was nausea (n=2). NVL-520 PK analyses demonstrated dose-dependent exposure. Among 12 efficacy-evaluable patients with ROS1+ NSCLC treated at 25-75 mg QD, 6 confirmed partial responses (PRs) were achieved. Shrinkage or resolution of intracranial metastases were observed; no patients had intracranial progression. A PR was achieved in most (n=5/7) ROS1 G2032R-mutant cancers, including lorlatinib or repotrectinib pretreated tumors. Circulating tumor DNA analyses showed reductions of ROS1 variant allele frequency. The RP2D has not been identified and dose escalation continues.
CONCLUSIONS: NVL-520 has been well-tolerated up to 100 mg daily with favorable pharmacokinetics. Activity has been demonstrated in heavily pretreated patients (of whom 70% received ≥2 prior ROS1 TKIs plus chemotherapy), including those with brain metastases and the G2032R mutation.
Pan-AKT Inhibitor Tumor Agnostic Targeting was Safe and Effective in Phase One Study
BARCELONA, Spain—Patients with solid tumors expressing mutated AKT oncogenes responded to therapy with a pan-AKT inhibitor ipatasertib in a phase one study reported at the 2022 EORTC—NCI—AACR symposium on Molecular Targets and Cancer Therapeutics.
Nearly a quarter of the patients treated with the AKT blocker had their tumors shrink. These included patients with breast, endometrial cancer and salivary gland cancers. And tumors remained stable in just over half of the remaining patients.
The first author at the Barcelona symposium, Kevin Kalinsky MD MS, Director of Breast Medical Oncology, Emory University at Winship Cancer Institute, Hematology and Medical Oncology, Atlanta, USA talks with Peter Goodwin.
BARCELONA, Spain—Although having a mutated MYC molecule is a distinguishing molecular factor in many solid tumors it has been considered “undruggable” — having a shortage of potential and actual mechanisms for cancer inhibition. But it now looks as though MYC could be a viable target for cancer drugs. A phase one study of a “pan-MYC inhibitor” OMO 103 has made promising findings in both safety and efficacy according to a findings given to the 2022 EORTC-NCI-AACR symposium.
First author of the study, Elena Garralda MD, Head of Early Drug Development Unit at Vall d'Hebron Hospital in Barcelona gave the Audio Journal of Oncology’s Peter Goodwin the details:
New Molecular Drug has Clinical Activity in Hepatocellular Carcinoma
Interview with:
Maria Reig MD PhD, Professor and Head of the Barcelona Clinic Liver Cancer (BCLC) Unit, Hospital Clinic Barcelona at Barcelona University, Spain.
BARCELONA, Spain—A phase one study of new drug targeting the monopolar spindle 1 enzyme was found to be safe—with reversible neutropenia as the commonest side effect—and to have clinical activity in patients with relapsed or refractory unresectable hepatocellular carcinoma (HCC). Maria Reig MD PhD announced the study findings at the 2022 European Organisation for Research and Treatment of Cancer-National Cancer Institute-American Association for Cancer Research (EORTC-NCI-AACR) Symposium on Molecular Targets and Cancer Therapeutics.
She gave the Audio Journal of Oncology’s Peter Goodwin more details of this new type of treatment, that she says works in a very different way from the current options for treating liver cancer.
PARIS, France—Patients who had cell therapy as second-line treatment for their advanced melanoma lived twice as long without disease progression compared with those who merely continued with pure immunotherapy. This finding came from a phase three randomized study reported at the 2022 Congress of the European Society for Medical Oncology (ESMO) by Amsterdam-based researchers, who said some of the patients may have been cured.
The second-line cell therapy consisted of re-infusion of autologous tumor infiltrating cells that had been harvested from patients own tumors and expanded ex-vivo. This followed initial immunotherapy with the checkpoint inhibitor ipilimumab.
The Audio Journal of Oncology hears from first author John B. Haanen MD PhD, Leader of Immunotherapy Research and Consultant in Medical Oncology at the Netherlands Cancer Institute in Amsterdam, in discussion with Peter Goodwin.
BARCELONA, Spain—Next generation sequencing is now an essential part of care for glioma in adults, according to research on BRAF targeting as treatment for this disease reported at the 2022 EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium.
Karisa Schreck MD PhD, from Johns Hopkins Hospital, Baltimore, Maryland in the USA talked with Peter Goodwin to discuss her team’s findings from a study looking at the relationship between BRAF oncogene mutations and anti-BRAF therapy outcomes in comparison with pediatric glioma treatment, for which BRAF targeting is already data driven.
She tells the Audio Journal of Oncology how the findings have brought clarity to therapy decision-making with adult patients who have glioma and test positive for BRAF oncogene mutations—and that some of them could potentially be treated with existing BRAF-targeted drugs that have already been licensed for use in other BRAF-driven cancers.
PARIS, France—the open-label international phase three randomized IPSOS study reported at the 2022 European Society for Medical Oncology congress that patients with non-small cell lung cancer who were not fit enough to be recommended standard platinum doublet chemotherapy lived longer when treated with the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab than patients in a comparison group who received a single-agent chemotherapy regimen.
https://cslide.ctimeetingtech.com/esmo2022/attendee/confcal/session/calendar/2022-09-12
Faced with the reality that a large unfit population of patients with non-small cell lung cancer cannot be recommended standard treatment (and who typically received single agent chemotherapy, or best supportive car) Siow Ming Lee, PhD FRCP, IPSOS Trial Chair, Professor of Medical Oncology and Consultant Medical Oncologist at University College London Hospital, told the Audio Journal of Oncology’s Peter Goodwin how they investigated the use of single-agent atezolizumab checkpoint inhibition immunotherapy in patients deliberately chosen for their low performance status who had no proven options for initial treatment.
Breast Conservation: Machine-Learning Helps De-Escalate Breast Cancer Therapy
André Pfob, Clinical Research Assistant in the University Breast Unit of Heidelberg University Hospital, Germany tells the Audio Jounal of Oncology’s correspondent Peter Goodwin about the machine learning techniques his group has been using to help identify patients who can be spared further treatment after neo-adjuvant therapy.
REFERENCE:
Annals of Surgery
https://journals.lww.com/annalsofsurgery/Abstract/9000/Towards_Patient_Centered_Decision_Making_in_Breast.93648.aspx
ABSTRACT:
Objective:
We developed, tested, and validated machine learning algorithms to predict individual patient-reported outcomes at 1-year follow-up to facilitate individualized, patient-centered decision-making for women with breast cancer.
Summary Background Data:
Satisfaction with breasts is a key outcome for women undergoing cancer-related mastectomy and reconstruction. Current decision-making relies on group-level evidence which may lead to sub-optimal treatment recommendations for individuals.
Methods:
We trained, tested, and validated three machine learning algorithms using data from 1921 women undergoing cancer-related mastectomy and reconstruction conducted at eleven study sites in North America from 2011 to 2016. Data from 1921 women undergoing cancer-related mastectomy and reconstruction were collected prior to surgery and at 1-year follow-up. Data from 10 of the 11 sites was randomly split into training and test samples (2:1 ratio) to develop and test three algorithms (logistic regression with elastic net penalty, Extreme Gradient Boosting tree, and neural network) which were further validated using the additional site's data.
Accuracy and area-under-the-receiver-operating-characteristics-curve (AUC) to predict clinically-significant changes in satisfaction with breasts at 1-year follow-up using the validated BREAST-Q were the outcome measures.
Results:
The three algorithms performed equally well when predicting both improved or decreased satisfaction with breasts in both testing and validation datasets: For the testing dataset median accuracy= 0.81 (range 0.73–0.83), median AUC= 0.84 (range 0.78–0.85). For the validation dataset median accuracy= 0.83 (range 0.81–0.84), median AUC= 0.86 (range 0.83–0.89).
Conclusion:
Individual patient-reported outcomes can be accurately predicted using machine learning algorithms, which may facilitate individualized, patient-centered decision-making for women undergoing breast cancer treatment.
PARP-Inhibition Beyond Initial Therapy Extends Life with Advanced Ovarian Cancer
PARIS, France—Long remissions and “potential cures” were reported at the 2022 Annual Meeting of the European Society for Medical Oncology (ESMO) in patients with newly diagnosed advanced ovarian cancers expressing the BRCA mutation who were treated with the poly ADP ribose polymerase (PARP) inhibitor olaparib after initial therapy.
Two thirds of women were alive seven years later in the phase three SOLO1 trial of olaparib maintenance therapy compared with placebo. The lead author of the study, Paul DiSilvestro MD, Professor in the Department of Obstetrics & Gynecology and Director of the Program of Women's Oncology at Women & Infants Hospital, Brown University in Providence Rhode Island, gives the details to the Audio Journal of Oncology’s Peter Goodwin.
Audio Journal of Oncology: Progression to Acute Myeloid Leukemia Explained by Multi Omics Analysis
A new research method has elucidated cellular processes (involving mutated TP53 oncogene) that can convert a relatively benign myeloproliferative neoplasm into a threatening acute myeloid leukemia.
Findings from Oxford University in the UK—using the novel genetic sequencing tool: single cell multi omics—were reported at the ASH Plenary Session, by Oxford scientist Alba Rodriguez-Meira—winner of an ASH Abstract Achievement Award.
In this episode of the Audio Journal, Alba Rodriguez-Meira DPhil, PhD, from the Weatherall Institute of Molecular Medicine in Oxford discusses her award-winning research with Peter Goodwin.
ATLANTA, USA— In an inspiring presentation at the American Society of Hematology (ASH) 2021 Annual Meeting Plenary Session, Alba Rodriguez-Meira PhD, from the Weatherall Institute of Molecular Medicine at Oxford University in the UK, explained how her group’s (ASH Abstract Achievement Award-winning) research on the TP53 gene had made it possible to analyze the genome of a large number of individual cells from a relatively small sample of patients and healthy controls. https://ash.confex.com/ash/2021/webprogram/Paper150191.html
The study findings should provide predictive, prognostic and therapeutic tools that could improve otherwise dismal outcomes in subgroups of patients with hematologic malignancies.
“Our single cell multi omics analysis, coupled with in-vitro and in-vivo analysis, has allowed us to depict a model of TP53 -mediated transformation in myeloproliferative neoplasms in which inflammatory signaling leads to suppression of wild-type and MPN cells while giving a fitness advantage to TP53 [mutated] cells with leukemic stem-cell properties. From our study we hope to find this is applicable to many other cancer types,” said Rodriguez-Meira at the ASH session.
Single-cell multi omics analysis in a small patient cohort can theoretically be used to derive the gene signature that is highly relevant in much larger patient cohorts.
Audio Journal of Oncology
September 9, 2022
“PM 2.5” Evidence Links Particulate Air Pollution to Non-Small Cell Lung Cancer
By Peter M Goodwin
PARIS, France—Particulate air pollution was identified as a key step in malignant transformation from benign DNA to non-small cell lung cancer according to a report delivered to the 2022 Congress of the European Society for Medical Oncology (ESMO).
Charles Swanton FRCP BSc PhD, Professor and Senior Group Leader of the Francis Crick Institute, Consultant Oncologist at University College London Hospital specializing in Thoracic Oncology and ESMO Scientific Co-Chair, told the Audio Journal of Oncology that prevention was better than cure wherever possible, and that the oncogenic mechanisms his group’s research had uncovered held important keys to reducing the cancer burden globally.
https://cslide.ctimeetingtech.com/esmo2022/attendee/confcal/session/calendar/2022-09-09
Swanton’s group had investigated the relationship between air pollution and lung cancer in never smokers. “We’ve tried to establish how air pollution causes lung cancer,” he told OT. “Through a series of steps involving animal models and human analyses we’ve found that air pollution results in the release of a cytokine called: interleukin 1-beta from epithelial cells in the lung, that generates and transforms cells with pre-existing mutations—that occur normally due to aging—into tumor cells.”
He discussed his findings during the ESMO congress in Paris with the Audio Journal of Oncology’s Peter Goodwin.
UK & NETHERLANDS—Following the the AJO Podcast interview with Professor Harry de Koning MD PhD, from the Erasmus University in Rotterdam, who discussed his research published in the New England Journal of Medicine that supports the widespread introduction of computed tomographic (CT) screening to detect lung cancer, this edition of the podcast hears from Professor David Baldwin MD, from Nottingham England, who comments on the clinical implications of these findings.
ROTTERDAM—Erasmus University Medical Center—The New England Journal of Medicine paper has confirmed the viability of computed tomographic (CT) screening for detecting cases of lung cancer early in high-risk individuals—namely those who smoke heavily and or have done so for decades.
A big new randomized study has confirmed that many deaths from lung cancer could be prevented by continuing and augmenting the global roll-out of computed tomographic (CT) screening for long-term heavy smokers. This follows important findings from the USA in which CT scanning was compared with chest X-ray for lung cancer detection that also came to the conclusion that many deaths from lung cancer can be prevented. Now that the professional community has confirmation from a separate study in a different continent with an alternative method of assessing CT (volumetric) the case for using CT screening for lung cancer may be considered to be convincing.
The Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON) population-based randomized controlled trial published in the New England Journal of Medicine emphasises the pivotal importance of addressing the epidemic of lung cancer which even today accounts for nearly a fifth of all cancer deaths worldwide. https://www.nejm.org/doi/full/10.1056/NEJMoa1911793
In the Audio Journal of Oncology podcast first author Harry de Koning, MD PhD, Professor of Public Health at Erasmus MC University Medical Centre in Rotterdam, the Netherlands, told reporter Peter Goodwin how a 24 per cent reduction in lung cancer mortality was found among men (after 10 years follow up) in the screening arm as compared to the control arm. Women did even better. Koning makes the case for global adoption of CT scanning as a key method of reducing cancer deaths, which he says can be done at an affordable cost. In this interview David Baldwin MD puts the research into global focus holding out the prospect for preventing deaths from lung cancer.
Second Study Confirms Lung Cancer CT Screening Cuts Deaths
NETHERLANDS—Erasmus University Medical Center, Rotterdam—Research published in the New England Journal of Medicine has confirmed the viability of computed tomographic (CT) screening for detecting cases of lung cancer early in high-risk individuals—namely those who smoke heavily and or have done so for decades.
A big new randomized study has confirmed that many deaths from lung cancer could be prevented by continuing and augmenting the global roll-out of computed tomographic (CT) screening for long-term heavy smokers. This follows important findings from the USA in which CT scanning was compared with chest X-ray for lung cancer detection that also came to the conclusion that many deaths from lung cancer can be prevented. Now that the professional community has confirmation from a separate study in a different continent with an alternative method of assessing CT (volumetric) the case for using CT screening for lung cancer may be considered to be convincing.
The Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON) population-based randomized controlled trial published in the New England Journal of Medicine emphasises the pivotal importance of addressing the epidemic of lung cancer which even today accounts for nearly a fifth of all cancer deaths worldwide. https://www.nejm.org/doi/full/10.1056/NEJMoa1911793
In the Audio Journal of Oncology podcast first author Harry de Koning, MD PhD, Professor of Public Health at Erasmus MC University Medical Centre in Rotterdam, the Netherlands, tells reporter Peter Goodwin how a 24 per cent reduction in lung cancer mortality was found among men (after 10 years follow up) in the screening arm as compared to the control arm. Women did even better. Koning makes the case for global adoption of CT scanning as a key method of reducing cancer deaths, which he says can be done at an affordable cost.
Audio Journal of Oncology
SAN DIEGO—The first-line treatment of choice for older patients with chronic lymphocytic leukemia (CLL) should now be single agent ibrutinib according to conclusions drawn from the Alliance North American Intergroup Study A041202 reported at the 2018 Annual Meeting of the American Society of Hematology (ASH).
https://ashpublications.org/blood/article/132/Supplement%201/6/265980/Ibrutinib-Alone-or-in-Combination-with-Rituximab
“Unless there is a good reason why patients should be on bendamustine plus rituximab (meaning that they are inappropriate for ibrutinib) ibrutinib is the most reasonable choice for front line therapy,” said lead study author Jennifer A. Woyach MD, an associate professor at the Ohio State University Comprehensive Cancer Center of Ohio State University in Columbus, OH.
Woyach told a press briefing that when they randomized patients “one to one to one” between three options for treatment: bendamustine plus rituximab, ibrutinib given as a single agent daily until disease progression, or ibrutinib given in combination with rituximab, there was a clear superiority for the ibrutinib-containing regimens.
“Progression-free survival was longer in the two ibrutinib-containing arms than in the bendamustine plus rituximab arm. And there was no difference in the progression-free survival between the two ibrutinib-containing arms.”
Woyach said they had conducted the trial to try to define the most optimal therapy for older patients with CLL. “We know that those patients are under-represented in many of our clinical trials,” she said. “So it’s hard to know whether much of our therapy can be extrapolated to this older patient group.”
Since ibrutinib had already been compared in earlier studies to chlorambucil in the phase three setting (leading to its FDA approval) it had never been compared to a chemo-immuntherapy regimen used in the CLL, she said. “So we tried to pick the most effective immunochemotherapy regimen for older patients—which is bendamustine plus rituximab—so that there would really be an effective comparator.”
In Woyach’s data there was no difference in progression free survival between patients treated with ibrutinib alone and those who received ibrutinib plus rituximab. “So ibrutinib alone would be the standard,” she said.
When she was asked about her choice of bendamustine plus rituximab as the comparator treatment she said there had been two reasons. Of the two chemo-immunotherapy regimens used in older patients (bendamustine plus rituximab and chlorambucil plus obinutuzumab) at the time the study was designed only the bendamustine regimen had been FDA approved, she said. “[But] regardless of that bendamistine plus rituximab does have superior progression free survival when you look at comparing across studies,” said Woyach.
Her interpretation of the study results? “For most patients this tells us that ibrutinib is the most effective drug for front-line CLL,” she said.
Microbiome Diversity Key To Survival After Allogeneic Hematopoietic Cell Transplantation
The Audio Journal of Oncology Podcast
SAN DIEGO—Overall survival after allogeneic hematopoietic cell transplantation (allo-HCT) was found to be adversely influenced by a lack of diversity in the intestinal microbiota—before, during and after the transplant—in a study from four research centers in three countries reported at the 2018 annual meeting of the American Society of Hematology.
https://ash.confex.com/ash/2018/webprogram/Paper116967.html https://www.ncbi.nlm.nih.gov/pubmed/31289031 https://www.ncbi.nlm.nih.gov/pubmed/31262981 https://www.ncbi.nlm.nih.gov/pubmed/31010813
Microbiome injury
The study found patterns of “microbiome injury” were strikingly comparable from country to country and from one transplant center to another—even when patients had different baseline microbiomes and the centers had different antibiotic practices, Jonathan Peled MD PhD, a bone marrow transplant physician at Memorial Sloan Kettering Cancer Center, New York told the Audio Journal of Oncology. “The implication is that associations observed in one center—or interventions that are observed to work in a trial at one center—are likely to be applicable broadly,” he said.
“We hypothesize that the injury we observed during transplant is attributable to antibiotic exposures and to not eating much during the transplant—although the chemotherapy conditioning and other drugs could be playing a role too.”
“We’ve known from animal studies that intestinal microbiota has a really important impact on how an individual who has received a bone marrow transplant does,” said Peled. And so the aim of the study had been to investigate this in humans: “And not just in a single-center observational fashion but in a multi-center large cohort so that we could really try to answer these questions definitively,” he said. The study had been designed to find out whether the pre-transplant microbiome diversity in the intestine could predict patient outcome.
Bacterial diversity
Peled explained that intestinal diversity was a measures “richness”—how many unique bacterial species were present in a sample, and also “even-ness”—how evenly each species was distributed in the sample. Typically, healthy bacterial communities in the gut had very high diversities, he said. And one microbiome injury pattern—or dysbiosis—they had observed in transplant patients had been a severe loss of this diversity. “In transplant patients a loss of diversity is seen that’s more severe than in most so-called dysbiotic states in other clinical settings” he said.
The study found that low diversity—either pre-transplant or post transplant—predicted for poor outcomes with shorter overall survival, increased transplant-related mortality, and—in some sub-sets of patients—more graft versus host disease, said Peled. “The number one implication is that we need clinical trials to design or test strategies to remediate damage. And number two: It may well be that bacteria have a pathogenic role in the pathophysiology of graft versus host disease,” he said.
Samples
The researchers collected 1922 stool samples from 991 patients having allo-HCT—in the United States, Germany and Japan—at four transplant centers. Patients varied in their underlying diagnoses, donor-graft sources, conditioning intensities, and graft versus host disease (GVHD) prophylaxis. “This is the largest such cohort that’s been assembled to ask these kinds of questions to date. And a critical feature of the study is that although we collected samples from all over the world we analyzed them all in one laboratory to try to overcome some of the potential biases,” Peled said.
Consistent dysbiosis
On average patients from all four transplantation centers had reduced microbiota diversity—even before allo-HCT—than in samples from healthy volunteers. Among 753 patients those in the lowest quartile of pre-HCT microbiota diversity had lower overall survival than those in the highest quartile. The investigators concluded that microbiota injury after transplant had been preceded by bacterial “community structures” that had already been abnormal at the start of the procedure. This explained why antibiotic exposure before transplant had been found to have been a risk factor for poor outcome.
Dominant bacteria
“Domination”—defined as one bacterial species populating at least thirty per cent of the microbiota—was found to be the injury most strongly associated with poor outcome. “In a bone-marrow transplant patient who is not eating, and has antibiotics “on board” for a week or more there can—in some cases—be only a single bacterium—mono-domination,” Peled said.
During transplantation the cumulative incidence of intestinal domination by any organism was more than 50 per cent at the outset and had become at least 87 per cent a month later. Such “low-diversity” states were found to be associated with exposure to broad-spectrum antibiotics, conditioning intensity, and low calorie intake.
Conclusions
The study concluded that microbiota configurations were similar in all four institutions as well as being distinct from those in healthy individuals. Also severe microbiota injury—including mono-domination—was commonly associated with allo-HCT. It began before allograft infusion, and microbiota injury before transplant predicted poor overall survival.
Interventions needed
They investigators suggested that the pre-transplant period was a window of opportunity to assess microbiota injury and to inform clinicians’ choice of antibiotic prophylaxis, approaches to gut-decontamination, GVHD-prophylaxis, and conditioning regimens. They concluded it was also a priority for researchers to look into ways of intervening to prevent or remedy microbiota injury.
“Judicious use of antibiotics—following guidelines such as those articulated by the Infectious Diseases Society of America—is always a good idea,” said Peled. “We’re not yet at the point where we can recommend changes to practice. But we are evaluating a potential recommendation in a randomized clinical trial.”
His center was comparing two different antibiotic strategies—the use of piperacillin-tazobactam and cephepime, Peled said. “In a prospective randomized clinical trial we’re randomizing patients to either of those two drugs as the first-line treatment for empiric fever-neutropenia. Our hypothesis is that: Piperacillin-tazobactam will be more deleterious to the flora and more deleterious for patient outcomes because it hits anaerobic bacteria. The results of this study may have implications about guidelines in the future.”
Equilibrium
Peled said that our immune system co-evolved with bacteria and depended on certain signals that emanated from the gut flora for its normal function. “So our microbiome and our immune system are existing in a constant dialogue—in an equilibrium—on a daily basis. You could even consider that, when you’re not sick, what your immune system is doing most of the time is maintaining this equilibrium,” he said.
On this model any immune reaction—be it auto-immune, anti-tumor, allo-immune, immune deficiency, or a response to an infection—could be viewed as a perturbation from that baseline equilibrium, he suggested. “So the more we can understand about how the host and the microbiome interact with one another at baseline, the [more] we can understand better what happens under states of perturbation,” he said.
Probiotics?
But Peled was not impressed by over-the-counter probiotic products. “They tend to include facultative aerobes—or at least bacteria that can tolerate oxygen. Whereas in contrast we find that most of the bacteria with benefits for patients are strict anaerobes. He did not recommend patients undergoing cancer therapy to stock up on any of the probiotics that are commercially available. “I don’t have data that it’s dangerous, but I don’t have any evidence that it’s beneficial,” he said. “On the other hand what would really be great would be to design a probiotic that is rationally designed and assembles just the right strains that we think will have the right effect,” he said. And he mentioned that he is beginning a research collaboration to develop probiotics that could be made available to patients.
Oncology practice
In daily practice cancer doctors needed to remember that everything they did had a potential downside and toxicity—and that we needed to test strategies to “dial back” the intensity and the duration of antibiotics. “So the busy cancer doctor should by all means treat fevers and infections in immune-compromised patients aggressively—according to guidelines—but we should be aware that there may be a down-side,” he said.
Audio Journal of Oncology
Reporting from 2018 annual meeting of the American Society of Hematology
SAN DIEGO—Individualized therapy decisions that are founded on “genomic fingerprint” data can now be made within seven days for most patients with suspected diagnoses of acute myeloid leukemia (AML) according to findings from the “Beat AML Umbrella Study for Previously Untreated AML” reported at the 2018 annual meeting of the American Society of Hematology (ASH). The research investigated the use of an algorithm combining data from clinical study evidence from trials with a range of targeted therapies. https://ashpublications.org/blood/article/132/Supplement%201/559/263190/Initial-Report-of-the-Beat-AML-Umbrella-Study-for
“I think it will be a huge paradigm shift for how AML is treated. We’ve really pushed the technology to its edge,” said study author Amy Burd PhD, of the Leukemia and Lymphoma Society, White Plains NY, at an ASH press briefing.
Real time
Being able to make treatment decisions within the seven-day period of time was becoming closer to the desired “real time” ability to make these decisions, she told the Audio Journal of Oncology. “With the number of targeted therapies that have been approved it provides the opportunity for doctors to make better choices for their patients.”
Algorithm
The study demonstrated that the algorithm was reducing the time taken for decision making in a disease that required prompt treatment, said Burd. The algorithm had used data on 11 out of the 12 prominent sub-types of mutations characterizing different forms of AML—including such molecular features as TP53, FLT3, IDH1, IDH2, core binding factor and NPM1.
She said the analysis achieved by the algorithm combined three different commercially available diagnostic assays. “We’ve been able to make assignments within the seven day period of time for over 95 per cent of the patients—achieving our primary endpoint of the study,” she said.
The Chief Medical Officer for the Beat AML Trial, John C. Byrd MD, Chair of Leukemia Research and Senior Advisor for Cancer Experimental Therapeutics at Ohio State University Comprehensive Cancer Center, Columbus OH, said that for many years acute myeloid leukemia—the most common adult leukemia—had been treated as a single disease but that science had prompted their study. “What all of the basic science has taught us is that AML is not a single disease but, likely, 15 or more diseases.”
Byrd said that in adults AML was characterized by so-called “driver mutations”—molecules that lead the bone marrow to perform abnormally. “Patients with AML will often have several of these—but one that’s dominant, and several that come later,” he said. “The significance of our trial is that we are looking at the different types of AML and prospectively picking the best therapy for the individual patient in a timely fashion.”
Dominant molecular driver
When he was asked about the diagnostic algorithm they had used in the study he said it had been based on the principle of looking for the dominant driver of the AML. “Do we have a therapy that’s going to be impactful for the biology? And do the patients fall into a small subgroup of patients where what we were doing before—chemotherapy—is really beneficial to them? If the standard is going to help patients we go with that,” he said, noting that the targeted therapies now offered options for the others.
Byrd likened targeting the dominant driver molecule as similar to cutting the trunk of a tree—all the branches die with the tree. “The benefits of the study are that patients are allowed to take advantage of all the technologies we have to pick the best therapy,” he said.
In the seven-day diagnostic time period this individualized approach allowed patients to become accommodated with their disease and avoid hazards such as post traumatic stress disorder from being rushed into therapy without being an active participant in the decision to treat their disease, he noted.
“This is the beginning. But it’s very exciting that we have been able to show that we can effectively assign therapy to more than 95 per cent of patients within seven days,” he said. “Precision medicine is here. And as new therapies come forward for AML we really need to be adopting this approach.”
SAN DIEGO—Patients 70 years old and younger with previously untreated chronic lymphocytic leukemia (CLL) lived longer and had progression of their disease delayed when treated with ibrutinib (an irreversible inhibitor of Bruton’s tyrosine kinase [BTK]) combined with the anti-CD 20 agent rituximab than patients in a control arm receiving standard fludarabine, cyclophosphamide and rituximab (FCR) in a phase three study from the ECOG-ACRIN Cancer Research Group reported to the 2018 annual meeting of the American Society of Hematology (ASH).
https://ash.confex.com/ash/2018/webprogram/Paper120779.html
New standard
The researchers concluded that the findings had immediate practice changing implications establishing ibrutinib-based therapy as the most effective first-line treatment for most patients with CLL. “Ibrutinib-based therapy is now the preferred initial treatment for the majority of CLL patients around the world independent of age,” said lead study author, Tait D Shanafelt MD, Professor of Hematology at Stanford University in Stanford CA, noting that a partner phase three study had also established its superiority in older patients. (Alliance North American Intergroup Study A041202: https://ash.confex.com/ash/2018/webprogram/Paper116653.html )
The “gold standard” treatment for younger patients—aged 70 and below—with previously untreated CLL (who were fit enough to tolerate aggressive treatment) had been FCR chemotherapy, said Shanafelt. “This trial evaluated whether the combination of ibrutinib and rituximab was similar to—or superior than—FCR-based therapy for these younger fit patients,” he said.
FCR toxic and not curative
At an ASH press briefing to announce the new findings Shanafelt told Oncology Times that although FCR had been the single best initial treatment for CLL, it had still not been a curative therapy. “And it’s also a fairly toxic treatment with extensive side effects,” he said. “It’s a regimen that can only be tolerated by CLL patients under 70—who tend to be more robust. So although it’s a good therapy, there’s room for improved effectiveness and certainly also room for improved side effect profile,” he said.
B-cell signaling
Ibrutinib targets Bruton’s tyrosine kinase (the enzyme that helps mediate cell signaling through the B-cell receptor pathway)—known to be an important survival pathway in CLL B-cells, said Shanafelt. “We know that it is very effective in relapsed patients—and can lead to very durable remissions,” he said. But it’s recent approval as an option for previously untreated patients had been based on a trial in elderly patients with CLL that compared ibrutinib to chlorambucil. “The challenge is that chlorambucil is a pretty ineffective treatment by itself for patients with CLL,” he said. “And the fact that ibrutinib was superior to chlorambucil didn’t really help us understand how it stacked up to our gold-standard treatments for CLL patients such as FCR,” he said.
Study
In the study the investigators enrolled 529 patients with previously untreated CLL who were aged 70 and younger. “We excluded patients with deletion 17p because that subgroup of patients does not respond well to FCR. So they were inappropriate to be randomized,” said Shanafelt. Two out of every three patients were randomized to ibrutinib plus rituximab, the remaining one-third of study patients received standard FCR—six cycles at “traditional dosing”, he said (intravenous fludarabine (25 mg/m2 ) and cyclophosphamide (250 mg/m2) days 1-3 with rituximab (50 mg/m2 on day 1 of cycle 1; 325 mg/m2 on day 2 of cycle 1; 500 mg/m2 on day 1 of cycles 2-6) every 28-days).
Results
After 34 months of follow up the ibrutinab/rituximab combination had conferred a superior progression free survival (PFS) as well as a superior overall survival (OS), he said. “The risk of progression was reduced by about two-thirds in the ibrutinib and rituximab arm compared to FCR. What was notable was that the ibrutinib and rituximab [regimen] was also less toxic than FCR with respect to the proportion of patients experiencing any grade three or higher toxicity. So we have a circumstance where the novel targeted therapy led to superior progression free survival, better overall survival, with fewer side effects.”
The researchers reported a benefit for PFS that favored the experimental arm over the FCR treatment arm with a hazard ratio (HR) of 0.352 (“p value” less than <0.0001). The HR for OS also favored the ibrutinib-based regimen with a HR of 0.168 (“p-value” of 0.0003).
Striking benefit
When he was asked about the striking benefit in OS from the experimental regimen Shanafelt said that although the improvement had been impressive “from a hazard ratio point of view”, there had been only a limited number of deaths on the trial. “So we probably need to be somewhat circumspect and desire longer follow up for that end-point,” he said. Even so (from the raw data) the risk of death had been reduced five-fold with ibrutinib-based therapy compared FCR, he said. “That difference was statistically significant and it met the criteria for superiority that was specified in the protocol before the trial began.”
“We were all surprised to see this early difference in the survival curves. And even though we’re encouraged by that I do think that we’re all wanting longer follow up to see how durable that is and whether the curves separate more widely or not,” he said.
How significant had been the reduction in PFS of about a 65 per cent by the time of follow up? “I think it’s impressive. It’s notable that the FCR-treated patients in this trial had progression free survival and overall survival exactly as expected—based on the previous German trials. So we see that the FCR patients did as we expected. But the ibrutinib arm was superior,” he said.
He added that neither arm of the study had reached the median PFS, and that it would need longer follow up before the researchers could assess medians for the two arms.
Toxicity
When he was asked about toxicities Shanafelt said the ibrutinib regimen had been less toxic overall and had different toxicities from FCR chemotherapy. “For the FCR arm grade three or higher adverse events occurred in a bit over 70 per cent of patients. In the ibrutinib-rituximab arm it was about 58 per cent,” he said. “If we look at all grade three and higher adverse events the toxicity [profile] favors ibrutiib and rituximab,” he said.
Different
There were big differences in the types of side effects, he said. “The grade three and higher adverse events that were more common in the FCR arm were myelo-suppression, neutropenia, low hemoglobin, low platelets and infectious complications. In the ibrutinib arm the side effects that were seen more frequently were atrial fibrillation (which occurred in three per cent of patients in the ibrutinib arm compared to no patients in the FCR arm) and hypertension (seven per cent of the patients in the ibrutinib arm compared to no patients in the FCR arm): So a slightly different side-effect profile.”
Shanafelt said the clinical implications were that ibrutinib-based therapy had been superior to the historical “best therapy” for treatment of CLL—which had been a chemotherapy platform of FCR. “It’s also less toxic than that historical therapy,” he said,
“The other exciting thing at this 2018 ASH meeting is that the Alliance [North American Intergroup Study A041202] presented the results in the plenary session of a companion study—a phase three trial—that looked at older patients: those age 65 and older, and compared ibrutinib or ibrutinib and rituximab to bendamustine and rituximab,” he said. These two trials had been designed in collaboration. And they had both reported reaching their primary endpoints of improving progression free survival with ibrutinib-based therapy over standard chemotherapy—the ECOG trial also showing a survival advantage, he said. “And together those two trials move us fully into the novel therapy era for treatment of CLL, and establish ibrutinib-based therapy as a preferred initial therapy for most patients with this disease.”
SAN DIEGO—Patients 70 years old and younger with previously untreated chronic lymphocytic leukemia (CLL) lived longer and had progression of their disease delayed when treated with ibrutinib (an irreversible inhibitor of Bruton’s tyrosine kinase [BTK]) combined with the anti-CD 20 agent rituximab than patients in a control arm receiving standard fludarabine, cyclophosphamide and rituximab (FCR) in a phase three study from the ECOG-ACRIN Cancer Research Group reported to the 2018 annual meeting of the American Society of Hematology (ASH).
https://ash.confex.com/ash/2018/webprogram/Paper120779.html
New standard
The researchers concluded that the findings had immediate practice changing implications establishing ibrutinib-based therapy as the most effective first-line treatment for most patients with CLL. “Ibrutinib-based therapy is now the preferred initial treatment for the majority of CLL patients around the world independent of age,” said lead study author, Tait D Shanafelt MD, Professor of Hematology at Stanford University in Stanford CA, noting that a partner phase three study had also established its superiority in older patients. (Alliance North American Intergroup Study A041202: https://ash.confex.com/ash/2018/webprogram/Paper116653.html )
The “gold standard” treatment for younger patients—aged 70 and below—with previously untreated CLL (who were fit enough to tolerate aggressive treatment) had been FCR chemotherapy, said Shanafelt. “This trial evaluated whether the combination of ibrutinib and rituximab was similar to—or superior than—FCR-based therapy for these younger fit patients,” he said.
FCR toxic and not curative
At an ASH press briefing to announce the new findings Shanafelt told OncologyPod that although FCR had been the single best initial treatment for CLL, it had still not been a curative therapy. “And it’s also a fairly toxic treatment with extensive side effects,” he said. “It’s a regimen that can only be tolerated by CLL patients under 70—who tend to be more robust. So although it’s a good therapy, there’s room for improved effectiveness and certainly also room for improved side effect profile,” he said.
B-cell signaling
Ibrutinib targets Bruton’s tyrosine kinase (the enzyme that helps mediate cell signaling through the B-cell receptor pathway)—known to be an important survival pathway in CLL B-cells, said Shanafelt. “We know that it is very effective in relapsed patients—and can lead to very durable remissions,” he said. But it’s recent approval as an option for previously untreated patients had been based on a trial in elderly patients with CLL that compared ibrutinib to chlorambucil. “The challenge is that chlorambucil is a pretty ineffective treatment by itself for patients with CLL,” he said. “And the fact that ibrutinib was superior to chlorambucil didn’t really help us understand how it stacked up to our gold-standard treatments for CLL patients such as FCR,” he said.
Study
In the study the investigators enrolled 529 patients with previously untreated CLL who were aged 70 and younger. “We excluded patients with deletion 17p because that subgroup of patients does not respond well to FCR. So they were inappropriate to be randomized,” said Shanafelt. Two out of every three patients were randomized to ibrutinib plus rituximab, the remaining one-third of study patients received standard FCR—six cycles at “traditional dosing”, he said (intravenous fludarabine (25 mg/m2 ) and cyclophosphamide (250 mg/m2) days 1-3 with rituximab (50 mg/m2 on day 1 of cycle 1; 325 mg/m2 on day 2 of cycle 1; 500 mg/m2 on day 1 of cycles 2-6) every 28-days).
Results
After 34 months of follow up the ibrutinab/rituximab combination had conferred a superior progression free survival (PFS) as well as a superior overall survival (OS), he said. “The risk of progression was reduced by about two-thirds in the ibrutinib and rituximab arm compared to FCR. What was notable was that the ibrutinib and rituximab [regimen] was also less toxic than FCR with respect to the proportion of patients experiencing any grade three or higher toxicity. So we have a circumstance where the novel targeted therapy led to superior progression free survival, better overall survival, with fewer side effects.”
The researchers reported a benefit for PFS that favored the experimental arm over the FCR treatment arm with a hazard ratio (HR) of 0.352 (“p value” less than <0.0001). The HR for OS also favored the ibrutinib-based regimen with a HR of 0.168 (“p-value” of 0.0003).
Striking benefit
When he was asked about the striking benefit in OS from the experimental regimen Shanafelt said that although the improvement had been impressive “from a hazard ratio point of view”, there had been only a limited number of deaths on the trial. “So we probably need to be somewhat circumspect and desire longer follow up for that end-point,” he said. Even so (from the raw data) the risk of death had been reduced five-fold with ibrutinib-based therapy compared FCR, he said. “That difference was statistically significant and it met the criteria for superiority that was specified in the protocol before the trial began.”
“We were all surprised to see this early difference in the survival curves. And even though we’re encouraged by that I do think that we’re all wanting longer follow up to see how durable that is and whether the curves separate more widely or not,” he said.
How significant had been the reduction in PFS of about a 65 per cent by the time of follow up? “I think it’s impressive. It’s notable that the FCR-treated patients in this trial had progression free survival and overall survival exactly as expected—based on the previous German trials. So we see that the FCR patients did as we expected. But the ibrutinib arm was superior,” he said.
He added that neither arm of the study had reached the median PFS, and that it would need longer follow up before the researchers could assess medians for the two arms.
Toxicity
When he was asked about toxicities Shanafelt said the ibrutinib regimen had been less toxic overall and had different toxicities from FCR chemotherapy. “For the FCR arm grade three or higher adverse events occurred in a bit over 70 per cent of patients. In the ibrutinib-rituximab arm it was about 58 per cent,” he said. “If we look at all grade three and higher adverse events the toxicity [profile] favors ibrutiib and rituximab,” he said.
Different
There were big differences in the types of side effects, he said. “The grade three and higher adverse events that were more common in the FCR arm were myelo-suppression, neutropenia, low hemoglobin, low platelets and infectious complications. In the ibrutinib arm the side effects that were seen more frequently were atrial fibrillation (which occurred in three per cent of patients in the ibrutinib arm compared to no patients in the FCR arm) and hypertension (seven per cent of the patients in the ibrutinib arm compared to no patients in the FCR arm): So a slightly different side-effect profile.”
Shanafelt said the clinical implications were that ibrutinib-based therapy had been superior to the historical “best therapy” for treatment of CLL—which had been a chemotherapy platform of FCR. “It’s also less toxic than that historical therapy,” he said,
“The other exciting thing at this 2018 ASH meeting is that the Alliance [North American Intergroup Study A041202] presented the results in the plenary session of a companion study—a phase three trial—that looked at older patients: those age 65 and older, and compared ibrutinib or ibrutinib and rituximab to bendamustine and rituximab,” he said. These two trials had been designed in collaboration. And they had both reported reaching their primary endpoints of improving progression free survival with ibrutinib-based therapy over standard chemotherapy—the ECOG trial also showing a survival advantage, he said. “And together those two trials move us fully into the novel therapy era for treatment of CLL, and establish ibrutinib-based therapy as a preferred initial therapy for most patients with this disease.”
MUNICH—A “salutary lesson” was reported by researchers investigating therapy for oropharyngeal cancer at the 2018 annual congress of the European Society for Medical Oncology (ESMO). It came from results of the De-ESCALaTE HPVstudy that found patients with low-risk head and neck cancer who tested positive for human papilloma virus (HPV+) did better if they had been treated with standard platinum-based chemotherapy (added their radiotherapy) rather than the epidermal growth factor receptor (EGFR) inhibitor cetuximab.
https://cslide.ctimeetingtech.com/esmo2018/attendee/confcal/session/calendar?q=+LBA9_PR
Phase three trials needed
“One of the big lessons is that you really need phase three trials—even when treatments are already approved—as in [the] case [of] head and neck cancer,” said Hisham Mehanna PhD BMed Sci FRCS, Chair of Head and Neck Surgery at the Institute for Head and Neck Studies Education in the University of Birmingham, UK. “You need phase three trials to compare new treatments to standards of care to really be able to take [them] into the clinic,” he told the Audio Journal of Oncology. “Clinical practice should not be changed without these phase three trials.”
Detriment from cetuximab
TheDe-ESCALaTE HPV study—reported at ESMO by Mehanna and his colleagues—found there had been “significant detriment from the use of cetuximab instead of cisplatin in terms of tumor control and no benefit in terms of reduced toxicity. They concluded that: “Cisplatin and radiotherapy remained the standard of care in this setting.”
MUNICH—A leading European oncologist acknowledged the impressive life-extending potential of new drug combinations for metastatic renal cell carcinoma discussed at the 2018 annual congress of the European Society for Medical Oncology (ESMO). Progress was reported with purely immunological approaches—using two different programmed death ligand 1 (PD-L1) targeted immunotherapies together—and also with therapies combining immunotherapy with tyrosine kinase inhibitors (TKIs) of vascular endothelial growth factor (VEGF).
Although such combinations had improved progression free survival (PFS) and even promised prolongation of overall survival (OS) the lack of comparisons between them left clinicians with little guidance—other than toxicity profiles—upon which to individualize treatment for their patients.
No biomarkers
“Unfortunately we don’t have good biomarkers that would help us selecting patients who would benefit either from immunotherapy alone, VEGF targeting agents alone, or the combination. So we have to look at the safety profiles of the combinations that we have right now—either the combinations with immunotherapies (alone) or the combination of a VEGF targeting agent and an anti PD-L1 drug—and see what would be the best for the patient that you have in front of you,” the Audio Journal of Oncology heard from John B.A.G. Haanen MD PhD, Chief Scientific Officer Immunotherapy and Consultant Medical Oncologist in the Division of Medical Oncology and Immunotherapy at the Netherlands Cancer Institute in Amsterdam.
MUNICH— A doubling of progression free survival (PFS) and objective response rate (ORR) was observed in patients who had their previously untreated advanced renal cell cancer (RCC) treated with a combination of the vascular endothelial growth factor (VEGF) inhibitor axitinib plus the anti-programmed death one ligand (PD-L1) avelumab in comparison with those receiving standard sunitinib anti-VEGF therapy in the randomized phase threeJAVELIN Renal 101 clinical trial. Findings were reported at the 2018 annual congress of the European Society for Medical Oncology (ESMO). http://212.114.167.162/slidecenter/esmo2018/attendee/confcal/session/calendar?q=LBA6_PR
Robust PFS
“The progression free survival was so robust, the objective response rate was robust [and] the safety profile was favorable that [this] warrants this combination as a new standard of care in patients with advanced kidney cancer,” lead investigator of the study Robert J Motzer MD PhD, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York told the Audio Journal of Oncology.
MUNICH— Anaplastic lymphoma kinase (ALK) inhibitors are as effective in “real world” clinical use for treating patients with non-small cell lung cancer (NSCLC) who test positive for ALK gene rearrangements as they are in clinical studies—even though randomized trials “cherry pick” patients to get statistically valid results. This is the conclusion of a retrospective analysis of data reported at the 2018 annual congress of the European Society for Medical Oncology (ESMO). http://212.114.167.162/slidecenter/esmo2018/attendee/confcal/session/calendar?q=jahanzeb
Progression free survival (PFS) was prolonged to a median of 7.4 months in the overall group of patients treated with ALK-targeted agents. “We were delighted to find out that these patients do as well as patients on clinical trials,” said author Mohammad Jahanzeb MD, Professor of Clinical Medicine, Hematology-Oncology and Medical Director of the University of Miami Sylvester Comprehensive Cancer Center in Deerfield Florida talking to the Audio Journal of Oncology. “Median progression free survival was in the same ball-park as we see in clinical trials.”
Jahanzeb said that prospective clinical trials excluded many real world patients who had comorbid conditions and factors such as brain metastases—which were often encountered among typical real-world patients. “So we thought it was really important to go to a database repository and do a “deep-dive” on the subset of patients positive for ALK,” he said, noting that half of these patients typically had brain metastases.
MUNICH—The role of poly ADP ribose polymerase (PARP) inhibitors for treating newly diagnosed advanced ovarian cancer was under review at the 2018 annual congress of the European Society for Medical Oncology (ESMO) in the light of findings from the SOLO1 randomized phase three trial in which there was more than a doubling of the numbers of patients surviving three years without disease recurrence in patients with BRCA gene mutations who were treated with olaparib after initial chemotherapy compared with similar patients receiving a placebo.
http://212.114.167.162/slidecenter/esmo2018/attendee/confcal/session/calendar?q=LBA7_PR
Unique
Commenting on the findings Jonathan Ledermann MD FRCP Professor of Medical Oncology, Director of the UCL Cancer Trials Centre and Clinical Director at the UCL Cancer Institute in University College London said the study had been a first. “We know that olaparib and other PARP inhibitors are very successful in delaying disease progression in patients with recurrent disease. But this trial tested maintenance olaparib in the front-line setting after surgery and chemotherapy—and that was unique,” he tells the Audio Journal of Oncology.
BRCA1/2 Ovarian Cancer—Three Years Disease Free with First-Line Olaparib
MUNICH—An “unprecedented improvement” in progression free survival (PFS) was observed in the randomized controlled double-blind phase three SOLO1 study of women with newly diagnosed ovarian cancer who had BRCA1/2 mutations and were treated with the poly ADP ribose polymerase (PARP) inhibitor olaparib after their standard initial platinum-based induction chemotherapy.
A three years extension of median PFS and the expectation of a robust superiority in overall survival (OS)—compared with the patients who had placebo therapy following their platinum induction chemotherapy—were reported at the 2018 annual congress of the European Society for Medical Oncology, ESMO.
http://212.114.167.162/slidecenter/esmo2018/attendee/confcal/session/calendar?q=LBA7_PR
Patients will demand
“It’s practice changing. Patients are going to be demanding this when these results are made public. I think rightly so,” said first author Kathleen Moore MD, Associate Director for Clinical Research at the Stephenson Cancer Center, University of Oklahoma in Oklahoma City. “We’re going to need to get the drug approved in this line—it’s not approved in front-line [therapy] in any part of the world,” she told the Audio Journal of Oncology.
MUNICH— Immunotherapy with the anti programmed death ligand 1 (PD-L1) checkpoint inhibitor atezolizumab in combination with nab-paclitaxel chemotherapy prolonged progression-free survival (PFS) among patients with metastatic triple-negative breast cancer in the randomized phase three IMpassion130 trial reported at the 2018 annual congress of the European Society for Medical Oncology, ESMO.
https://www.nejm.org/doi/full/10.1056/NEJMoa1809615?query=featured_home
The experimental treatment also prolonged overall survival (OS) in patients who tested positive for PD-L1—the molecular target of atezolizumab.
Transformative
“For me this is practice-changing. This is a massive step. This is the first time—a clear improvement in overall survival, not just a marginal improvement. We see a transformative benefit of nearly ten months based on survival in the control group of only 15 months. So it’s more than a 50 per cent improvement in overall survival which is a very meaningful result for patients with this difficult-to-treat sub-type of breast cancer.”
So said first author of the IMpassion130 trial Peter Schmid MD PhD, Chair of Oncology at Barts Cancer Institute and Queen Mary University of London and Director of St. Bartholomew’s Breast Cancer Centre in London UK in conversation with the Audio Journal of Oncology.
MUNICH—A combination of the phosphoinositide 3-kinase (PI3K) inhibitor alpelisib plus fulvestrant significantly extended progression free survival (PFS) compared to placebo plus fulvestrant in patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer in the randomized phase three SOLAR-1 trial reported at the 2018 annual congress of the European Society for Medical Oncology, ESMO.
“This study opens the door for precision medicine in metastatic breast cancer,” said lead investigator Fabrice André MD PhD, Associate Professor in the Department of Medical Oncology at Institut Gustave Roussy in Villejuif, France. This had been the first study to show statistically significant clinically meaningful PFS improvement with an alpha isoform-specific PI3K inhibitor in patients with HR+ HER2- advanced breast cancer and mutated oncogene PIK3CA, he said, and the drug had a “manageable toxicity profile”.
“[This] alpha selective PI3 kinas inhibitor improves progression free survival in a clinically meaningful way in patients who present [with] mutational PI3 kinase,” André tells the Audio Journal of Oncology. He noted that SOLAR-1 had been the first study to show a benefit from a targeted therapy driven by genomics.
MUNICH—Patients with hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer who were treated with a combination of the cyclin dependent kinase (CDK) 4/6 inhibitor palbociclib in combination with fulvestrantlived longer than those receiving a placebo with fulvestrant in the prospective, randomized, double-blind, phase three PALOMA-3 study from which overall survival (OS) data were reported at the 2018 annual congress of the European Society for Medical Oncology, ESMO.
http://212.114.167.162/slidecenter/esmo2018/attendee/confcal/session/calendar?q=LBA2_PR
New standard
“This combination should be the standard of care for patients progressing on endocrine therapy,” said PALOMA-3 study senior investigator Massimo Cristofanilli MD FACP, Professor of Medicine at the Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University in Chicago IL. He tells the Audio Journal of Oncology: “There’s no doubt there is a clinical and meaningful strong benefit—not only in delaying the disease but also [in] survival. This should replace the use of chemotherapy,” he said.
The trial found that patients taking the CDK4/6 inhibitor with fulvestrant lived a median of 6.9 months longer than those in the control group treated with placebo and fulvestrant.
MUNICH—More than four years median overall survival was reported in patients treated with an inhibitor of anaplastic lymphoma kinase (ALK) for their ALK gene rearranged non-small cell lung cancer (NSCLC) in a single-arm phase two study reported at the 2018 annual congress of the European Society for Medical Oncology, ESMO.
http://212.114.167.162/slidecenter/esmo2018/attendee/confcal/session/calendar?q=felip
“The information presented here showed that for patients included in the ASCEND 3 trial—ALK positive patients previously treated with chemotherapy—who received ceritinib as their first ALK inhibitor there [was] an overall survival of 51 months. This is really encouraging,” said lead author Enriqueta Felip MD PhD, medical oncologist and Chair of the Thoracic Malignancies Group at Vall d’Hebron University Hospital in Barcelona, Spain, talking to the Audio Journal of Oncology.
Reporter: Sarah Maxwell
BARCELONA—Pembrolizumab did not significantly improve overall survival (OS) or progression free survival (PFS) compared with paclitaxel as second-line therapy in patients with advanced gastric or gastro-esophageal junction cancer that had progressed after one line of chemotherapy (containing a platinum and fluoropyrimidine) in the KEYNOTE-061 randomized open-label controlled phase three trial reported at the ESMO 20th World Congress on Gastrointestinal Cancer. https://www.ncbi.nlm.nih.gov/pubmed/29880231.
Molecular Biomarker
The lack of statistical benefit was despite the fact that the analysis was with patientswho had been selected because they had programmed cell death ligand 1 (PD-L1) combined positive scores (CPS) of 1 or higher—indicating at least a one per cent positive staining rate in their tumors—marking them as theoretically ideal candidates for therapy with this checkpoint inhibitor antibody that targets programmed cell death 1 (PD-1) molecular features.
The findings call into question the simplistic concept that targeting a molecular feature on a particular tumor will necessarily be sufficient to work as a method of treating that cancer.
Sub-Groups
But lead author Kohei Shitara MD, Chief Doctor in the gastrointestinal department of the National Cancer Center Hospital East in Kashiwa, Japan, said that sub-group analysis yielded positive findings for some patients and that pembrolizumab had a better safety profile than paclitaxel.
He tells the Audio Journal of Oncology: “The trial did not meet the primary endpoints to show survival improvement [or] PFS improvement,” he said. But some of the patients showed “very durable benefit” with pembrolizumab. The sub-group study confirmed that patients with good performance status and having at least 10 per cent staining for PD-L1 expression (defined as a CPS score of 10) had improved prospects—as did those with tumors expressing high microsatellite instability (MSI).
BARCELONA—Oral cabozantinib “significantly improved” overall survival (OS) and progression free survival (PFS) compared to placebo in patients with advanced hepatocellular carcinoma(HCC) whose disease had progressed despite sorafenib therapy in the phase 3 CELESTIAL trial reported to the 2018 ESMO World Congress on Gastrointesinal Cancer.
http://ascopubs.org/doi/abs/10.1200/JCO.2018.36.4_suppl.207
“This is a new oral drug [that’s] very easy for the patient to take at home. And it works for some patients. When it works it can work very well. It can prolong life—and with very good responses in some patients in terms of tumor necrosis, tumor shrinkage, tumor de-vascularization. It’s well tolerated and it’s a new tool to fight against cancer,” according to study co-author Philippe Merle MD PhD, a hepato-gastro oncologist and medical oncologist at the Hospice Civile de Lyon University Hospital in Lyon, France. He discusses the CELESTIAL trial and it's clinical implications with the Audio Journal of Oncology's Sarah Maxwell.
BARCELONA—A chemotherapy combination consisting of trifluridine with tipiracil showed a “clinically meaningful and statistically significant” improvement in overall survival (OS) and progression free survival (PFS) compared with placebo in patients with heavily-pretreated metastatic gastric cancer (mGC) refractory to standard therapies in the randomized phase three TAGS study reported at the ESMO 20th World Congress on Gastrointestinal Cancer. https://academic.oup.com/annonc/article/29/suppl_5/mdy208.001/5043314
“The TAGS study has shown in a randomized phase three setting that trifluridine-tipiracil is an available option for treating patients with gastric or gastro-esoophageal cancer in the metastatic refractory setting,” said lead author Josep Tabernero MD PhD, Chair of Medical Oncology at Vall d'Hebron University Hospital in Barcelona, Spain in this edition of the Audio Journal of Oncology.
Patients lived a median of 5.7 months when treated with the new combination compared with 3.6 months in the control group receiving best supportive care—a 2.1 months extension of life and a 31 per cent reduction in the risk of death (hazard ratio: 0.69).
Professor David Cunningham MD FRCP, Consultant Medical Oncologist and Director of Clinical Research at the Royal Marsden Hospital, London adds his comments about the role of this combination in gastric cancer in the clinic.
CHICAGO—A 25 per cent risk reduction for esophageal cancer was found to be associated with prophylactic therapy consisting of a proton pump inhibitor (PPI) and aspirin in the phase three randomized ASPECT multicenter study from the United Kingdom reported at the 2018 Annual Meeting of the American Society of Clinical Oncology (ASCO).
https://meetinglibrary.asco.org/record/160062/abstract
The trial investigated long-term daily high doses of esomeprazole (80 mg or 20 mg daily) together with aspirin (300 mg) among 2563 patients who had Barrett’s Esophagus (BE) and were therefore at high risk of the disease.
Although the study focused on people with Barrett’s Esophagus, lead study author Janusz Jankowski, MD, PhD, Deputy Vice Chancellor, Royal College of Surgeons, Ireland and Consultant Clinical Adviser, National Institute for Health and Care Excellence, UK told the Audio Journal of Oncology he believed that any person with heartburn could consider taking a high-dose proton pump inhibitor and aspirin after speaking with their doctor. But he warned that patients should not self-medicate since the benefits so far had been found in the specific subset of patients who had BE.
CHICAGO—Patients with resectable and “borderline resectable” pancreatic cancers treated with chemoradiation before surgery (followed by adjuvant chemotherapy) had significantly improved outcomes compared to those randomized to have surgery first and adjuvant chemotherapy in the Dutch Pancreatic Cancer Group’sPREOPANC-1 randomized, controlled, multicenter phase III trialreported at the 2018 Annual Meeting of the American Society of Clinical Oncology (ASCO).
https://meetinglibrary.asco.org/record/160063/abstract
Although fewer tumors could be resected in patients treated with preoperative therapy compared with those on standard care (down from 72 to 62 per cent) there was a markedly increased rate of complete resections, said study author Geertjan Van Tienhoven MD, PhD, a radiation oncologist at the Academic Medical Center in Amsterdam, Netherlands, who is a member of the Dutch Pancreatic Cancer Group. He discusses the PREOPANC-1 study implications with the Audio Journal of Oncology.
CHICAGO—Clinically targetable mutations were identified and patient subgroups pinpointed by whole genome sampling (WGS) of castration-resistant metastatic prostate cancer (mPC) in a study reportedatthe 2018 Annual Meeting of the American Society of Clinical Oncology. (https://meetinglibrary.asco.org/record/160671/abstract)
Lisanne F van Dessel MD, a medical oncologist at Erasmus Medical Center Cancer Institute in Rotterdam, The Netherlands, tells the Audio Journal of Onclogy that while their research confirmed that this disease was complex and unstable they had found potentially actionable targets waiting to be studied for therapeutic use which were also likely to be prognostic, predictive or both.
CHICAGO—A gene test that predicts for relapse in women with estrogen receptor positive early breast cancer can identify patients with low-risk disease who could safely avoid extending their endocrine therapy beyond the standard five years, according to study findings reported in a poster session at the 2018 Annual Meeting of the American Society of Clinical Oncology (ASCO).
https://meetinglibrary.asco.org/record/162390/abstract
Co-author Graham M Poage PhD, a scientist with the Biotheranostics Company based in La Jolla, California tells the Audio Journal of Oncology about the “Breast Cancer Index” (BCI) test—a reverse transcription polymerase chain reaction (RT-PCR) 11-gene assay—was an endocrine-therapy decision-making tool that had identified very low risk—patients who had 20-year breast cancer specific survival of 98 per cent—a significant proportion of patients who, potentially, could be spared extended endocrine therapy because their risk is so low that continued therapy is unlikely to benefit [them].
CHICAGO—Men who had breast-conserving therapy (BCT) including radiation for their early breast cancer lived longer than those who had total or partial mastectomy—with or without radiation—in findings from a large retrospective survey of male breast cancer reported at the 2018 Annual Meeting of the American Society of Clinical Oncology (ASCO).
https://meetinglibrary.asco.org/record/162945/abstract
In a poster presentation at ASCO Sarah Bateni MD, a surgery resident at the University of California Davis Medical Center in Sacramento, reported survival outcomes from an analysis of National Cancer Database (NCDB) records of 11,406 men who had stage one, two or three breast cancer between the years 2004 and 2015. She discusses the findings with the Audio Journal of Oncology in the company of her colleague, Candice A. M. Sauder, MD, MEd, a Breast Surgical Oncologist at University of California Davis Medical Center.
CHICAGO—Women and men were treated differently for the same tumor stages of head and neck cancer (HNC) and had different outcomes in a study with patients surveyed over a fifteen-year period in Santa Clara, California. The findings—using the generalized competing event (GCE) assessment model that balanced the risk of cancer death against non-cancer death—has prompted a call to reassess the influence of gender on treatment decision-making.
Study author Jed A. Katzel MD, a medical oncologist with Kaiser Permanente in Santa Clara, talks with the Audio Journal of Onclogy about his new data from GCE modeling he reported at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO).
(Abstract LBA6002: Are women with head and neck cancer undertreated?)
https://meetinglibrary.asco.org/record/161984/abstract
Commenting on the findings ASCO Expert Joshua A Jones, MD MA, a radiation oncologist at the Perelman School of Medicine at University of Pennsylvania in Philadelphia said: “We don’t know why women are getting less treatment and having worse outcomes and we need to find out. Though these findings are specific to California the disparities we see are startling and worth considering in treatment discussions in everyday practice.”
CHICAGO, IL—Patients whose non-small cell lung cancers (NSCLC) expressed more than one per cent of the programmed death ligand-1 (PD-L1) tumor proportion score (TPS) lived longer when treated with the anti programmed death 1 (PD-1) antibody pembrolizumab than a control group of patients receiving platinum-based chemotherapy in the open-label, phase three KEYNOTE-042 study reported at the American Society of Clinical Oncology (ASCO) annual meeting plenary session. https://meetinglibrary.asco.org/record/165950/abstract
Better survival
Principal author of the study, Gilberto Lopes MD, Associate Professor of Clinical Medicine at the University of Miami’s Sylvester Comprehensive Cancer Center tells the Audio Journal of Onclogy patients treated with pebrolizumab monotherapy lived a median of four to eight months longer than those who received chemotherapy and had fewer severe side effects than with chemotherapy (18 per cent as compared with 41 per cent).
CHICAGO—Prophylactic contralateral (CLT) breast radiotherapy was associated with significantly fewer and delayed cases of breast cancer in women having standard therapy for their ipsilateral BRCA mutation-associated breast cancers in a study from Israel reported in a poster session at the American Society of Clinical Oncology 2018 annual meeting.
https://meetinglibrary.asco.org/record/161629/abstract
(Phase II national clinical trial of prophylactic irradiation to the contralateral breast for BRCA mutation carriers treated for early breast cancer.)
Jewish women, high risk
Ella Evron MD, a medical oncologist at the Kaplan hospital in Zerifin, Israel, said that in Israel they saw many patients with BRCA-associated breast cancer because three “founder mutations” are commonly detected in Ashkenazi Jews who are at very high risk of developing breast cancer. She tells the Audio Journal of Oncology about the opportunity to study prophylactic radiotherapy because women increased risk of getting contralateral breast cancer were declining prophylactic surgery because of the fear of its impact on their lives.
BARCELONA—Handgrip strength (HGS) was found to be an independent quantitative marker for overall survival among patients with early-stage non-small cell lung cancer (NSCLC) being treated with stereotactic body radiotherapy (SBRT) in a study discussed at the 2018 European Society for Radiotherapy & Oncology (ESTRO 37) conference.
ABSTRACT: PV-0041 Hand grip strength: independent prognostic selection test for OS in stage I NSCLC treated with SBRT
https://cld.bz/5RlE5Z/26/
The investigators used a handgrip strength test before patients were treated with SBRT and followed them up for survival. First author Stéphanie Peeters MD PhD, a radiation oncologist from the MAASTRO Clinic in Maastricht, Netherlands tells the Audio Journal of Onclogy how they saw that there was indeed a correlation between a weak handgrip strength and overall survival and only 12 per cent of patients with handgrip weakness were alive five years later compared with 40 per cent of those who had normal handgrip.
The President of ESTRO Yolande Lievens MD PhD, head of the department of radiation oncology at Ghent University Hospital in Belgium, comments about the study findings.
BARCELONA—Accelerated partial breast irradiation (ABPI) brachytherapy completed in a single week gave at least as good efficacy and safety as other radiotherapy protocols after breast-conserving therapy (BCS) for patients with low-risk breast cancer and brought advantages in terms of symptoms and convenience in a randomized phase three trial(conducted at 16 European medical centers)reported at the 2018 European Society for Radiotherapy & Oncology (ESTRO 37) conference. (OC-0326 QOL After APBI (Multicatheter Brachytherapy) Versus WBI: 5-Year Results, Phase 3 GEC-ESTRO Trial)
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30195-5/abstract
“We really have to consider further reducing treatment burden for patients with low-risk breast cancer,” said radiation oncologist Philip Poortmans MD PhD, past ESTRO president, Marie Curie Professor and head of department at Paris Science & Lettres, Institut Curie in Paris commenting on the study findings. “And an excellent approach to this is accelerated partial breast irradiation—for which brachytherapy is an excellent solution,”
First author Rebekka Schäfer MD, Resident Medical Doctor at Würzburg University Hospital in Würzburg, Germany talks with the Audio Journal of Oncology about her study in which APBI with brachytherapy was compared directly to whole breast irradiation in the study and was not inferior in terms of overall survival and local recurrence at five years.
Yolande Lievens MD PhD, head of the department of radiation oncology at Ghent University Hospital in Belgium, said the findings endorsed brachytherapy as an option which improved opportunities for individualizing therapy and limiting the volume of the breast being irradiated.
BARCELONA—Image-guided adaptive brachytherapy (IGABT) for patients with cervical cancer did not increase risk for ureteral stricture (a rare but feared complication of pelvic radiotherapy) in European research reported at the European Society for Radiotherapy & Oncology (ESTRO 37) 2018 conference.
(OC-0072 Risk factors for ureteral stricture after IGABT in cervical cancer: results from the EMBRACE studies)
https://user-swndwmf.cld.bz/ESTRO-36-Abstract-Book1
“Our findings show that the risks for severe to life-threatening ureteral strictures are very low in all the patients with limited stage disease,” said first author Lars Fokdal MD PhD, a clinical oncologist from Aarhus University Hospital in Denmark, who told the Audio Journal of Oncology about his group’s updated population-based findings and conclusions from analysis of data from 1772 patients treated with brachytherapy for their locally advanced cervical cancer (LACC) in the retrospective RetroEMBRACE study (with 610 patients) and the prospective EMBRACE (with 1162 patients).
BARCELONA—It is essential to conduct a comprehensive geriatric assessment of patients over 74 with lung cancer before deciding to escalate treatment dose by switching to concurrent chemo-radiotherapy in an attempt to improve outcomes. This was the conclusion of a phase 2 study reported at the European Society for Radiotherapy & Oncology (ESTRO 37) conference.
(PV-0039 Outcome of elderly NSCLC patients treated with isotoxic RT dose-escalation using IMRT—NCT01166204)
https://user-swndwmf.cld.bz/ESTRO-36-Abstract-Book1
Principal investigator Judith van Loon MD PhD, a radiation oncologist at MAASTRO Clinic in Maastricht, The Netherlands told the Audio Journal of Oncology that clinicians could do more harm than good with this treatment if they did not take into account other factors, and that this held true despite the fact that only patients who had excellent performance status were selected for such escalation.
BARCELONA—The accuracy of radiation targeting using image-guided radiotherapy (IGRT) was significantly associated with overall survival in a study of a large cohort of patients treated with IGRT for their lung and esophageal cancers. reported at the 2018 European Society For Radiotherapy and Oncology (ESTRO 37) annual conference (ABSTRACT OC-0322, “Residual setup errors after IGRT are linked to overall survival in lung and oesophageal cancers”)
Cardiotoxicity
The key hazard was found to be unintended irradiation of the heart. Patients who had residual set-up errors which moved their hearts closer to the high-dose region had significantly worse overall survival compared to those who had a residual shifts away from the heart said first author Corinne Johnson MSc, a physics PhD student at Christie NHS Foundation Trust, University of Manchester and Manchester Cancer Research Centre in the UK in conversation with the Audio Journal of Oncology.
BARCELONA—Women who develop breast symptoms—especially lumps—between regular mammography screening examinations are up to four times more likely to have a diagnosis of breast cancer soon after than women who do not have symptoms according to findings of a massive study of routine mammography from Finland reported at the 2018 European Breast Cancer Conference (EBCC 11).
“Women with symptoms should be taken as a different, separate group—a high risk group. So they will have different screening strategies from women without symptoms [with] more further assessment like ultrasound, further mammography or biopsy and close monitoring,” said study author Deependra Singh MPH who works in the Research Laboratory of the Finnish Cancer Registry in Helsinki, Finland.
ABSTRACT TITLE:
Breast symptoms and risk of interval breast cancers in mammography-screening programme
https://www.ecco-org.eu/Events/EBCC11/Searchable-Programme#anchorScpr
BARCELONA—More pre-menopausal women who have estrogen receptor (ER) positive advanced breast cancer could be spared chemotherapy—according to latest findings from the MONALEESA-7 double-blind randomized phase 3 trial in which either placebo (PBO) or the cyclin-dependent kinase (CDK) 4/6 inhibitor ribociclib (RIB) were added to tamoxifen (TAM) or a non-steroidal aromatase inhibitor (NSAI) with all patients also having ovarian suppression by goserelin therapy.
https://www.ecco-org.eu/Events/EBCC11/Searchable-Programme#anchorScpr
At the 2018 European Breast Cancer Conference (EBCC 11) Nadia Harbeck MD, Professor of Gynaecology and head of the Breast Center at the University of Munich in Germany said that following her group’s latest study findings practice should change for young, pre-menopausal patients who presented for the first time with hormone receptor positive human epidermal growth factor receptor2- (HER2)-negative advanced breast cancer. She discusses her findings with the Audio Journal of Oncology.
Emiel J T Rutgers MD PhD FRCS from the Netherlands Cancer Institute, Professor of Surgical Oncolology at the University of Amsterdam, who was not involved with the study, said the results were very interesting. “We have now another possibility added to our armamentarium. My opinion is that in pre-menopausal women who recur with hormone-sensitive estrogen-dependent breast cancer with visceral or bony metastasis a re-challenge with anti-hormonal treatment including ribociclib or a comparable [agent] is now the first option. And the side-effect profile is rather mild—so that’s another positive thing about it.”
LATE BREAKING ABSTRACT 1LBA:
Ribociclib (RIB) plus tamoxifen (TAM) or a non-steroidal aromatase inhibitor (NSAI) in premenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC): additional results from the MONALEESA-7 trial
https://www.ecco-org.eu/Events/EBCC11/Searchable-Programme#anchorScpr
BARCELONA—A multicenter nationwide Italian study of patients with ductal carcinoma in situ (DCIS) treated with breast conservative surgery (BCS) and whole breast radiotherapy (RT) has updated risk criteria to help women opt for gentler treatments and avoid toxicities from overtreatment.
At the 2018 European Breast Cancer Conference Icro Meattini MD, Consultant Clinical Oncologist in the Radiation Oncology Department at Azienda Ospedaliero-Universitaria Careggi, University of Florence, Italy said: “A diagnosis of DCIS can be frightening but also confusing. Although we know that very few patients will go on to develop invasive cancer we don’t know which ones they will be and so we offer treatments such as surgery and radiotherapy and sometimes hormone therapy.” He discusses the findings of his study with the Audio Journal of Oncology.
BARCELONA—Not only was breast conserving therapy safer than mastectomy for most low-risk patients in the large randomized EORTC 10041/BIG 03-04 MINDACT trial reported at the 2018 European Breast Cancer Conference but also many patients could be advised to avoid chemotherapy and radiotherapy altogether after assessing their risk as "low" by using a combination of clinical and genetic risk scores, the study concluded.
Emiel Rutgers MD, PhD, a surgeon at the Netherlands Cancer Institute and professor of surgical oncology at the University of Amsterdam said MINDACT found an overall five-year loco-regional recurrence rate of only 2.1 per cent in patients treated conservatively and 2.5 per cent in those who had mastectomy. Tumor size and grade were the only independent risk factors and the results provided “the opportunity to prospectively study de-escalation of radiotherapy in women with low-risk early breast cancer”. He discussed his study and the clinical implications for the Audio Journal of Oncology.
BARCELONA—Healthy women with BRCA1 mutations who opted for bilateral prophylactic mastectomy had their lives prolonged in comparison with similar women who did not. But in healthy women with the BRCA2 mutation the procedure did not improve overall survival even though it reduced their risk of breast cancer in the next ten years. These findings were reported at the 2018 European Breast Cancer Conference from an analysis of the Netherlands national Hereditary Breast and Ovarian Cancer Netherlands (HEBON) database.
First author Annette Hemskerk-Gerritsen PhD, a post-doctoral researcher at Erasmus Medical Center in Rotterdam, discusses the clinical implications of the study for the Audio Journal of Oncology.
BARCELONA—Patients treated for BRCA-associated breast cancers could be given more accurate estimates of the risk for developing second primaries of the contralateral breast by combining polygenic risk scores (PRS) with standard risk factors if study findings reported at the 2018 European Breast Cancer Conference are validated.
The AUDIO JOURNAL OF ONCOLOGY heard from lead author Alexandra van den Broek PhD, a genetic epidemiologist from the Netherlands Cancer Institute in Amsterdam, how the predictive power of PRSs for a first primary breast cancer in the general population and for BRCA 1 and 2 mutation carriers could also extend to forecasting second primaries of the contralateral breast enabling women to make more informed decisions about their on-going treatment options.
Isabel T. Rubio MD PhD, co-chair of the 11th European Breast Cancer Conference and Director of the Breast Surgical Unit at Clinica Universidad de Navarra, in Madrid, Spain who was not involved in the research said: “Facing a diagnosis of breast cancer and carrying a BRCA mutation is overwhelming for many women. New information on the individual risks of developing a contralateral breast cancer in this population will help in the decision-making process on preventive surgery or intensive follow up. Research like this brings new information to help with these difficult decisions.”
Abstract no: 7:
“The association between Polygenic Risk Scores and contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers: analyses in the CIMBA consortium”
https://www.ecco-org.eu/Global/News/EBCC/EBCC11/03/Risk-of-a-second-breast-cancer-can-be-better-quantified-in-women-carrying-a-BRCA-mutation
Read Peter Goodwin's article in ONCOLOGY TIMES
ATLANTA—Six months follow up of the Select-D randomized open label multicenter pilot study with 406 patients has confirmed that therapy with the direct oral anticoagulant (DOAC) rivaroxaban was a safe and effective alternative strategy to standard treatment with the low molecular weight heparin dalteparin for avoiding recurrences of venous thromboembolism (VTE) in selected patients with cancer. The findings were reported at the 2017 meeting of the American Society of Hematology. Abstract 625: Anticoagulation Therapy in Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism: Results of the Select-D Pilot Trial
“We found recurrence rates with dalteparin at six months were 11 per cent. With rivaroxaban the recurrence rates were four per cent,” said lead author Annie Young PhD, Professor of Nursing at Warwick Clinical Trials Unit in Warwick University Medical School’s Cancer Research Centre, UK. “Definitely we found that the rivaroxaban recurrence rates at six months were lower than dalteparin.”
READ MORE IN ONCOLOGY TIMES
ATLANTA—Six months follow up of the Select-D randomized open label multicenter pilot study with 406 patients has confirmed that therapy with the direct oral anticoagulant (DOAC) rivaroxaban was a safe and effective alternative strategy to standard treatment with the low molecular weight heparin dalteparin for avoiding recurrences of venous thromboembolism (VTE) in selected patients with cancer. The findings were reported at the 2017 meeting of the American Society of Hematology. Abstract 625: Anticoagulation Therapy in Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism: Results of the Select-D Pilot Trial
“We found recurrence rates with dalteparin at six months were 11 per cent. With rivaroxaban the recurrence rates were four per cent,” said lead author Annie Young PhD, Professor of Nursing at Warwick Clinical Trials Unit in Warwick University Medical School’s Cancer Research Centre, UK. “Definitely we found that the rivaroxaban recurrence rates at six months were lower than dalteparin.”
READ MORE IN ONCOLOGY TIMES
ATLANTA— In patients with a variety of cancers oral therapy with edoxaban—a direct oral anticoagulant (DOAC)—was just as effective and safe in terms of the risks of recurrent venous thromboembolism (VTE) and bleeding as injections with the low molecular weight heparin (LMWH) dalteparin in the multinational randomized Hokusai VTE-Cancer Study reported at the 2017 American Society of Hematology annual meeting.
LBA-6 A Randomized, Open-Label, Blinded Outcome Assessment Trial Evaluating the Efficacy and Safety of LMWH/Edoxaban Versus Dalteparin for Venous Thromboembolism Associated with Cancer: Hokusai VTE-Cancer Study
“[The] findings show that the edoxaban treatment is non-inferior to the low molecular weight heparin therapy,” said lead author Gary E. Raskob PhD, Dean of the College of Public Health and Professor of Medicine and Epidemiology at the University of Oklahoma in Oklahoma City.
READ MORE from the American Society of Hematology Meeting in Oncology Times.
ATLANTA—Adding anti-BCL-2 therapy with the small-molecule drug venetoclax (VEN) to standard low-dose cytarabine (LDAC) chemotherapy tripled response rates over historical comparators and extended survival in older patients with acute myeloid leukemia (AML) who were ineligible for intensification of their chemotherapy in a phase 1/2 study reported at the 2017 American Society of Hematology annual meeting.
ABSTRACT 890 Phase 1/2 Study of Venetoclax with Low-Dose Cytarabine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia Unfit for Intensive Chemotherapy: 1-Year Outcomes
“With this new combination we seem to achieve very high complete response rates. We achieve response quickly—which means that patients have better quality of life, potentially, and less risk of fatal infections and also less need for blood transfusions and supportive care,” said lead study author Andrew Wei MBBS PhD FRACP FRCPA, a clinical hematologist and head of leukemia research at the Alfred Hospital in Melbourne, Australia.
READ THE ARTICLE IN ONCOLOGY TIMES
MILAN, Italy—The first choice of therapy for patients with metastatic kidney cancer who have failed VEGF therapy has changed according to experts at the 2016 European Multidisciplinary Meeting on Urological Cancers (EMUC) who assessed phase 3 study data on two different agents—each of which showed clinically meaningful improvements to outcomes.
“There is a new treatment algorithm for individuals who have failed VEGF-targeted therapy,” said Thomas Powles, MBBS MRCP MD, Director of Barts Cancer Centre at St Bartholemews Hospital in London, UK.
“Both the ESMO and EAU guidelines are [now] supporting nivolumab and cabozantinib rather than—[as] previously—supporting axitinib and everolimus.”
He based his comments on observations from the METEOR and CheckMate 025 studies which found that therapy with cabozantinib or nivolumab improved overall survival compared to everolimus.
Peter Goodwin discusses the details of the METEOR findings with him.
MILAN, Italy—Patients with node-positive prostate cancer being treated with prostatectomy could derive benefit from early multimodality therapy combining androgen deprivation therapy (ADT) with radiotherapy (RT)—on top of surgery—if they have pathological features indicating high risk, according to findings reported at the European Multidisciplinary Meeting on Urological Cancers (EMUC).
Combining ADT with RT soon after prostatectomy improved overall survival as much as 40 per cent in the highest-risk patients according to analysis of data from studies conducted at three institutions—Memorial Sloan-Kettering Cancer Center in New York, the Mayo Clinic in Rochester MN and San Raffaele Hospital in Milan.
“It is the patients who are supposed—technically—to have the worst mortality from the disease that have the best survival when they receive the treatment,” said co-investigator Karim Touijer MD MPh, Attending Physician at the Department of Urology in the Sidney Kimmel Center for Prostate and Urologic Cancers at Memorial Sloan-Kettering Cancer Center in New York City.
He said that while the most common approach to node-positive disease after prostatectomy was observation—followed by treatment only if there was progression—his analysis suggested a potential net benefit from combining RT and ADT in patients who had additional risk factors on top of nodal spread.
He said studies were urgently needed to confirm any benefit since the natural history of patients with nodal disease after radical prostatectomy indicated that even—without further treatment—30 per cent of all patients were free from recurrence by 10 years. And this figure rose to 45 per cent among patients with only one or two nodes.
Pathological features can discriminate the 80 per cent of patients with nodal disease who had favorable characteristics and would be candidates for observation, he said. But it was important to identify those at the high risk because they could benefit from a multimodality approach, he said.
In his research from the three institutions patients with node-positive prostate cancer were divided into three groups after prostatectomy—those who had additional treatment with external beam RT, those who received the same RT combined with ADT, and patients assigned to no further treatment until relapse.
“We looked at a combined data set of nearly 1400 patients [who] received one of three strategies: Observed until they failed biochemically then treatment started, or: Automatically received hormonal therapy for life, or: Received the combination of hormonal and radiation therapy,” he said, adding that patients who received the combination of ADT and external beam RT started with the worst disease yet had the best overall survival.
Local Treatment Benefit
Touijer said they concluded there was great value in local control of the disease, despite the belief that if a patient had lymph-node metastases after radical prostatectomy the disease was already distant and systemic.
“What this data shows us is that maybe some patients are like that but not all of them, and not the majority, [and] that if we still focus—with all the treatments that we have available—to control the disease locally and regionally we can improve survival,” he said.
Not all Nodal Disease the Same
And analysis of the National Cancer Database (including 70 percent of all patients treated at US cancer centers) had given “external validation of these findings”.
“Close to 5 000 patients were treated by observation followed by treatment after failure, radiation alone, hormonal therapy alone, or a combination of hormonal and radiation therapy,” he said, noting that subcategories of patients with nodal disease clearly needed different treatment since there was a wide spectrum of risk and patients with the worst pathological features benefited the most from combining surgery, ADT and RT.
“We did statistical risk groups based on Gleason grade, clinical stage, invasion of the seminal vesicles, T4 disease, positive surgical margins—all the elements which have been shown to be predictive in most prostate cancers in many series. And the worse these features are the better the separation and the advantage in overall survival if we added radiation and hormone therapy,” he said.
ADT Monotherapy
The three-institutional data set revealed no difference in overall survival between patients who were observed and those treated with lifetime ADT.
“When we tried to look in detail at cancer-specific survival we saw that there was an advantage to androgen deprivation therapy. But when we looked at death from other causes—not cancer causes—we saw that there was [also] a detriment,” he said.
Radiation Therapy
Node-positive patients assigned after prostatectomy to RT alone lived longer than patients allocated to ADT alone.
“The assumption is that thorough surgery followed by radiation therapy is controlling the source of the disease and seems to make a difference in terms of survival. [But] the combination of both [ADT and RT] seems to give the best result.”
Caution
But Touijer repeated that prospective clinical trials were needed to remove potentially confounding variables in these retrospective data, warning that these therapies could also have deleterious effects.
“One always has to balance the risk and benefit. But in terms of survival it looks like multimodality therapy has a clear advantage,” he said.
Multidisciplinary Team
“A prudent way forward is for surgeons to reach out to radiation therapists and medical oncologists when they are dealing with patients [who] have lymph node metastases after radical prostatectomy and happen to have a Gleason 8, 9 or 10, pathological stage T3b or T4, positive surgical margins, and a higher nodal count and really carefully look at the value a multimodality approach for these patients—because it may alter their survival.”
Audio Journal of Oncology
AMSTERDAM—Women diagnosed with ductal carcinoma in situ (DCIS) of the breast were found to live longer than women in the general population according to a study from the Netherlands reported at the 2017 European Cancer Congress (ECCO).
Full Interview Transcript
LOTTE ELSHOF speaks with Peter Goodwin at the European Cancer Congress, ECCO 2017 in AMSTERDAM
Peter Goodwin
YOU WERE LOOKING AT CAUSE SPECIFIC MORTALITY IN PATIENTS WITH DCIS, WHAT WERE YOU TRYING TO DO IN THIS STUKDY?
Lotte Elshof
We looked at patients treated for DCIS – a potential precursor lesion to invasive breast cancer and we assessed cause specific mortality. So we looked at DCIS patients and during follow up see if they had died from what cause they had died and then we compared mortality with mortality in the general population. We wanted to look at [whether] DCIS patients had increased risk of dying.
WHY DID YOU WANT TO LOOK AT DCIS?
DCIS is a potential precursor to invasive breast cancer. So some DCIS lesions will progress into invasive breast cancer and invasive breast cancer can metastasise and then cause death so it’s an important thing to look at the outcomes of DCIS and there are a lot of uncertainties and anxiety associated with DCIS because many patients diagnosed with DCIS think they are diagnosed with breast cancer. But it’s not breast cancer, yet.
TELL ME WHAT YOU DID IN THE STUDY?
We looked at patients diagnosed with DCIS between 1989 and 2004 and we looked at the causes of death in this population and we compared these observed death numbers with the expected number of deaths.
QUITE A BIG GROUP?
Yes. Almost 10 000 women with DCIS
WHAT DID YOU FIND?
We found that DCIS patients older than 50 at diagnosis were at lower risk of dying compared to the general population. And—it may sound a bit counter-intuitive—but we think it is because these patients are mostly screen-detected so they go to the population-based screening program for breast cancer and these patients are likely to be more health conscious.
DETAILS—A THREE TIMES HIGHER RISK?
We saw that DCIS patients had lower risk of dying despite their increased risk of dying from breast cancer. So if you compare the risk of dying from breast cancer to the general population we see that they have an increased risk. But then if we look at absolute numbers—the risk a woman [actually] had—then the risk is very low. So after ten years 2.5 per cent of the women died from breast cancer but compared to the general population this is only slightly increased risk.
AND YOU ALSO MENTIONED THAT THE RISK OF DEATH FROM BREAST CANCER WAS INDEPENDENT OF TREATMENT?
Yes we found that no matter what treatment the risk of mortality was so low. So we compared women treated with breast conserving therapy alone, breast conserving therapy with radiotherapy, and mastectomy and we saw no differences in breast cancer mortality.
PRACTICAL MESSAGES FOR DOCS?
This study provides accurate risk estimates—relative risks and absolute risks— which are important information to the patient. And I think these patients should be told they have a precursor lesion of invasive breast cancer but not yet invasive breast cancer and it should provide reassurance.
WHAT DOES THIS IMPLY FOR LOOKING FOR DCIS BECAUSE MANY WOMEN GET WORRIED BY THE DIAGNOSIS?
Yes. It’s a very worrying diagnosis. It’s associated with a lot of anxiety and confusion. It means that we sometimes find lesions that we would have rather not detected but because of screening we will find those lesions and the screening program also has a lot of benefits. So it’s not that we say that we don’t need to screen but there are always harms against benefits and some DCIS detection would be beneficial.
YOU DON’T WANT TO COMMIT YOURSELF WHETHER IT’S BETTER TO HAVE KNOWLEDGE OF YOUR DCIS?
No. We cannot conclude that. We need more studies. More prospective studies and also we need to wait for the prospective studies on active surveillance of DCIS because at this moment we don’t have this information.
WHAT IS THE TAKE HOME MESSAGE FOR CANCER CLINICIANS?
Accurately explain the diagnosis of DCIS. Tell the patient what it is. And these women with screen-detected DCIS can be reassured that they have the same life expectancy as other women.
ARTICLE:
Women With DCIS Live Longer Than General Population
By Peter M Goodwin
AMSTERDAM—Women diagnosed with ductal carcinoma in situ (DCIS) of the breast were found to live longer than women in the general population according to a study from the Netherlands reported at the 2017 European Cancer Congress (ECCO).
“It may sound a bit counter-intuitive—but we found that DCIS patients older than 50 at diagnosis were at lower risk of dying compared to the general population,” said Lotte Elshof, MD PhD Student Associate of the Departments of Surgery, Epidemiology and Molecular Pathology at the Netherlands Cancer Institute in Amsterdam.
“We think it is because these patients are mostly screen-detected so they go to the population-based screening program for breast cancer and are likely to be more health conscious,” she said.
The findings she reported were associated with the on-going randomized, non-inferiority phase III “LORD” trial being conducted in the Netherlands by the BOOG (Borstkanker Onderzoek Groep) team under principal investigator Jelle Wesseling MD PhD, Consultant Breast Pathologist at the Netherlands Cancer Institute in Amsterdam looking at “management of low grade ductal carcinoma in situ: active surveillance or not?” https://www.boogstudycenter.nl/studie/276/lord.html
Elshof explained that they looked at patients being treated for DCIS because it was a potential precursor lesion to invasive breast cancer.
“If [patients] had died we assessed cause-specific mortality [to] see from what cause they had died. And then we compared [their] mortality with mortality in the general population,” she said.
The study found that patients with DCIS had lower risk of dying of all causes combined compared to the general population and “seem to represent a generally healthy subgroup.”
Also, their absolute risk of breast cancer death was low—3.9 percent at 15 years—and the risk of dying from breast cancer among women treated for DCIS alone was only slightly higher than that in the general population.
The suggestion was that “a history of primary DCIS has no negative effect on overall survival.”
The study looked at 9,799 women treated for DCIS in the Netherlands from 1989 to 2004. 1,429 deaths occurred over a median follow-up of 10 years of which 368 were due to cardiovascular disease (4 percent of the total population) and 284 deaths were due to breast cancer (3 percent).
These data revealed an overall risk of dying of all causes that was significantly lower combined compared to the general population.
“There are a lot of uncertainties and anxiety associated with DCIS because many patients think they are diagnosed with breast cancer. Some DCIS lesions will progress into invasive breast cancer and can metastasize and then cause death. So it’s an important to look at the outcomes,” Elshof said.
Breast Cancer-Specific Risk
Although the study confirmed that patients with DCIS were at increased risk of dying from breast cancer they still had a lower risk of dying overall despite this.
“If we look at absolute numbers the risk is very low,” she said. “After ten years 2.5 percent of the women died from breast cancer—but compared to the general population this is only a slightly increased risk.”
Intriguingly the study also found that the risk of dying from breast cancer was independent of the type of treatment patients received.
“We found that no matter what treatment, the risk of mortality was low. We compared women treated with breast conserving therapy alone, breast conserving therapy with radiotherapy, and mastectomy. And we saw no differences in breast cancer mortality,” she said.
When she was asked what was the practical message for cancer clinicians she said the study provided accurate estimates of relative and absolute risk which she regarded as important information for the patient.
“These patients should be told they have a precursor lesion of invasive breast cancer but not yet invasive breast cancer. And it should provide reassurance,” she said.
“[DCIS is] a very worrying diagnosis. It’s associated with a lot of anxiety and confusion. It means that we sometimes find lesions that we would have rather not detected. But because of screening we find those lesions and the screening program also has a lot of benefits. So it’s not that we say we don’t need to screen but [that] there are always harms against benefits. And some DCIS detection would be beneficial,” said Elshof.
She concluded that doctors could now accurately explain the diagnosis of DCIS, and tell patients what it is and reassure them they have the same life expectancy as other women.
Philip Poortmans MD PhD, President-elect of ECCO and head of the Radiation Oncology Department at Radboud University Medical Center in Nijmegen, in The Netherlands said that although ductal carcinoma in situ should be considered as being clearly different from breast cancer treatments had side-effects.
“This research provides reassurance for women with DCIS because it shows that they are as likely to be alive ten years after the diagnosis as people in the general population who did not have DCIS. This is also reassuring with regards to the potential risks of side-effects,” he said.
“However, we have to recognize that in one fifth of patients who die, the cause is breast cancer—which is likely to result from progression of the DCIS they were diagnosed with. Therefore, we are eagerly waiting results of further research to identify factors—including age, as clearly shown in this study—that contribute to the risk for recurrence and progression from DCIS for each individual patient.”
Poortmans thought it was remarkable that the increased risk of dying from breast cancer was completely offset by a lower risk of dying from other causes compared to women in the general population.
“This might be explained by the generally better health and socioeconomic status of women who regularly participate in breast cancer screening. This could also be tested in the on-going research,” he said.
Audio Journal of Oncology, January 2, 2017
COPENHAGEN—Patients with metastatic non-small cell lung cancers (NSCLC) expressing the programmed cell-death ligand 1 (PD-L1) protein responded better to initial treatment with the anti-PD-L1 immunotherapy pembrolizumab—and lived longer with fewer toxicities—than to standard chemotherapy in the international KEYNOTE-024 (NCT02142738) study reported to the European Society for Medical Oncology 2016 congress. (Abstract LBA8_PR.)
http://annonc.oxfordjournals.org/content/27/suppl_6/LBA8_PR.full?sid=57db4b00-dd13-4ca0-ac50-086c77db63c0
Lead author Martin Reck MD PhD, a thoracic oncologist from the Grosshansdorf Lung Clinic near Hamburg in Germany, said the open-label, phase 3 study compared pembrolizumab checkpoint inhibition with platinum-doublet chemotherapy as first-line therapy for patients whose lung cancers had PD-L1 tumor proportion scores (TPS) of 50 percent or greater and did not have treatable epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) translocations.
“These data are changing our management of patients with lung cancer,” he said adding that the results implied PD-L1 had emerged as an important predictive biomarker for treating patients with metastatic non-small cell lung cancer and that for patients whose tumors have it expressed pembrolizumab was an attractive new option in first-line treatment.
“The efficacy has been clearly better for pembrolizumab compared to chemotherapy, and the tolerability has been clearly better. So this tells us that we have to change our diagnostics for lung cancer. So besides the diagnostics for EGF receptor or ALK translocation we have to implement PD-L1 testing in our up-front diagnosis for lung cancer because we have got a completely new treatment option for this group of patients,” Reck told the Audio Journal of Oncology.
In the KEYNOTE-024 study patients with nonsquamous NSCLC were randomized either to 35 cycles of pembrolizumab, or between four and six cycles of investigators’ choice of platinum doublet chemotherapy (carboplatin or cisplatin plus pemetrexed, carboplatin or cisplatin with gemcitabine, or carboplatin plus paclitaxel) with optional pemetrexed maintenance.
The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), overall response rate (ORR), and safety.
After a median follow-up of 11.2 months, nearly half of the 305 patients randomized to pembrolizumab chose to continue with their allocated initial therapy while only ten percent of those in the chemotherapy arm opted to continue with their initial treatment. Crossover was allowed, and when the disease progressed 44 percent of patients initially assigned to chemotherapy crossed over to pembrolizumab.
Disease Progression
Patients initially assigned to treatment with pembrolizumab lived a median of more than ten months before their disease progressed compared with only six months for those receiving chemotherapy. The immunotherapy was also associated with higher ORR (45percent compared with 28 percent) and longer duration of response —the median was not reached in the pembrolizumab arm and was 6.3 months with chemotherapy.
Overall Survival
Six months after starting treatment 80 per cent of patients who started on pembrolizumab were alive compared with only 72 per cent for those initially allocated to chemotherapy. This was equivalent to a 40 per cent reduction of mortality risk for patients on pembrolizumab monotherapy—despite the high crossover rate.
Toxicities
Toxicities of any-grade were less common with immunotherapy (73 percent of patients had toxicities versus 90 percent with chemotherapy), and grade three-to-five treatment-related adverse events (AEs) were half as common with permbrolizumab. (27 percent versus 53 percent).
Stefan Zimmermann, MD, from Hôpital Fribourgeois, HFR Hôpital Cantonal, in Fribourg, Switzerland, who chaired a news briefing on the KEYNOTE-024 study at ESMO noted this was the first time that an immune-oncology strategy had been demonstrated in the first-line setting. “Until now we’ve seen a lot in second and third line or further lines of therapy,” said.
ESMO officer Solange Peters, MD PhD, Médecin Cheffe of Thoracic Malignancies, at the Centre Hospitalier Universitaire Vaudois (CHUV) at Lausanne University in Switzerland told OT the KEYNOTE-024 study had demonstrated that even though chemotherapy was already quite good this form of immunotherapy had made a further improvement.
“It’s an amazing set of data because for the first time our classical standard of care—platinum-based chemotherapy—is questioned. It was very improbable until now that new combinations or new agents would dramatically change the course of the disease by replacing platinum-based chemotherapy,” she said.
The KEYNOTE-024 study authors concluded that pembrolizumab had superior PFS and OS over platinum-based chemotherapy in patients with advanced NSCLC and PD-L1 expression (TPS) of at least 50 per cent, and that these findings—together with the lower rate of treatment-related AEs—implied that the drug may be the new standard of care for first-line therapy for this group of patients.
Reck said there was a clear message for clinicians. “Management of first-line therapy of patients with advanced non-small cell lung cancer has changed. We have to add the assessment of PD-L1 in our first-line diagnosis. We have a new group of patients identified that has a substantial benefit by a mono-therapy by an anti-immune treatment—the patients with high PD-L1 expression. We have to identify the patients up-front because we have to treat them up-front.”
COPENHAGEN—Longer progression free survival (PFS) was achieved in patients with ALK-rearranged non-small cell lung cancer (NSCLC) previously treated with crizotinib randomised to treatment with the second generation anaplastic lymphoma kinase (ALK) inhibitor ceritinib rather than chemotherapy in the phase 3 ASCEND 5 study reported to the European Society for Medical Oncology (ESMO) 2016 Congress. (Abstract LBA42_PR
http://www.esmo.org/Conferences/ESMO-2016-Congress/Press-Media/Ceritinib-Provides-Longer-Progression-free-Survival-Than-Chemotherapy-in-Phase-III-Trial-of-ALK-Rearranged-Lung-Cancer-Treatment )
“We have another active agent that should be implemented in the clinical armamentarium for those patients with lung cancer that is ALK-positive—a preferred option over chemotherapy,” said Giorgio Scagliotti MD PhD, Professor of Medical Oncology at the University of Turin, Italy in an interview with the Audio Journal of Oncology (AJO).
“Ceritinib is a second generation ALK inhibitor that is much more potent than crizotinib and the study was [with] patients who were already exposed to crizotinib and cytotoxic chemotherapy looking at ceritinib versus the standard treatment—pemetrexed or taxotere (docetaxel),” Scagliotti said.
The open-label ASCEND-5 study included 231 patients with NSCLC who had received crizotinib. The median PFS in patients then treated with ceritinib was 5.4 months as compared with 1.6 months for those receiving chemotherapy—a hazard ratio of 0.49 for PFS. Compared to chemotherapy ceritinib increased overall response rate (39.1 percent compared with 6.9 percent) but there was no improvement in overall survival with ceritinib.
“In this selected patient population, where the target is present, this drug can give very interesting PFS in second, third, or fourth line—as long as the tumor is not resistant to [it],” said ESMO officer Solange Peters MD PhD, Médecin Cheffe in the Department of Thoracic Malignancies at Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Switzerland.
Stefan Zimmermann MD, from the Hôpital Fribourgeois, HFR Hôpital Cantonal, Fribourg, Switzerland noted that ceritinib had demonstrated an advantage over standard chemotherapy in second and further lines of therapy. “But the real question is: What do we have to use in first line?” he asked.
Scagliotti welcomed the addition of ceritinib to the family of tyrosine kinases for the small subgroup of patients who have the ALK translocation genomic alteration. “The first in class was crizotinib—a highly effective agent inducing 70 per cent response rate, improving survival over cytotoxic chemotherapy as shown in the PROFILE studies. But the issue with targeted therapies is that sooner or later you get relapse or progression of the disease and patients develop resistance,” he said.
Toxicities
The most frequent grade three to four adverse events with ceritinib were nausea (7.8 percent), vomiting (7.8 percent) and diarrhoea (4.3 percent), and with chemotherapy were neutropenia (15.5 percent), fatigue (4.4 percent) and nausea (1.8 percent). Ceritinib significantly improved patient-reported outcomes including lung cancer-specific symptoms and overall health status, compared to placebo.
“The toxicity profile was exactly what we were expecting from previous studies with ceritinib—with ALK treatment-naïve and ALK-pretreated patients having more gastrointestinal toxicities with ceritinib and some liver function test elevations that were not clinically relevant. In patients who received docetaxel hematological toxicities were much more commonly reported,” Scagliotti said.
But he said it was too early to give clear clinical guidelines about using ceritinib since there had not yet been head-to-head comparisons with crizotinib, and other ALK inhibitors were under investigation. “We need to wait a few months to identify the right sequence among these different treatment options,’ he said.
But he was optimistic. “Having many treatment options is much better than to have only one treatment option,” he said, adding that ceritinib was now the preferred option for patients who had already been exposed to crizotinib.
While ceritinib was the only second generation ALK inhibitor so far licensed in Switzerland, giving it an advantage there for treating patients who had failed crizotinib, there were some outstanding issues, said Stefan Zimmerman—including gastrointestinal toxicity—which distinguished ceritinib from other second generation ALK inhibitors such as alectinib.
“This data has to be put in the context of the ALEX trial (http://meetinglibrary.asco.org/content/167434-176) which is going to change what we’ve seen from the data at ASCO [about] the way we treat these ALK-rearranged patients—meaning that we’ll most certainly be starting with second generation inhibitors up front in the hope that at least we can overcome this extremely high rate of cerebral progression which is a major issue with crizotinib and one of the major reasons why we do not like to use it and we—absolutely—are desperate for better agents,” he told the AJO.
Solange Peters said the ASCEND 5 study had successfully answered an important question. “Once you have given crizotinib and platinum-based chemotherapy what should you do? Should you go to the usual docetaxel or second-line chemotherapy or should you switch to a targeted therapy? And the answer is very clear. Targeted therapies are better than chemotherapy—very clear,” she said.
Drug Sequencing
Also commenting on the ASCEND 5 findings, Alice Tsang Shaw, MD, PhD, a thoracic oncologist at the Massachusetts General Hospital Cancer Center in Boston, MA, welcomed this first randomized study to examine how a second generation ALK inhibitor compared to standard second line chemotherapy in ALK positive patients who failed the standard first line therapy.
“Single arm studies have suggested that ceritinib and alectinib could be standard options in the second line setting after crizotinib has failed,” said Shaw. “The positive effect on progression-free survival in this phase 3 study confirms that there is greater benefit using a second ALK inhibitor over standard chemotherapy. This will establish sequential crizotinib followed by a second generation ALK inhibitor as the standard treatment for patients with metastatic ALK positive lung cancer.”
She added that they were all awaiting the outcome of studies testing the second generation ALK inhibitors ceritinib (versus chemotherapy) and alectinib (versus crizotinib) in the first-line setting. “The latter trial addresses one of the most fundamental questions in the field, which is what should be the first ALK inhibitor that patients receive?”
The Audio Journal of Oncology
Reporting from the 2016 Congress of the European Society of Medical Oncology
COPENHAGEN—The anti-PD-L1 (programmed cell death ligand-1) immunotherapy agent atezolizumab extended overall survival when compared head-to-head with docetaxel among patients with previously-treated non-small cell lung cancer (NSCLC) in the phase 3 OAK study reported at the European Society for Medical Oncology 2016 congress. (Abstract LBA44_PR http://annonc.oxfordjournals.org/content/27/suppl_6/LBA44_PR.short#)
Lead author Fabrice Barlesi MD PhD, Professor of Medicine at the Department of Multidisciplinary Oncology and Therapeutic Innovations of Assistance Publique Hôpitaux de Marseille, Aix-Marseille University in Marseille, France reported an overall hazard ratio of 0.73 in favor of immunotherapy among the first 850 patients—of whom those treated with atezolizumab lived more than four months longer than those receiving docetaxel (13.8 as compared with 9.6 months median).
Since the agent targets the PD-L1 protein it was expected to be more effective in patients testing positive for PD-L1, and the OAK study indeed found greater efficacy in this biomarker-positive group. Yet the drug clearly benefited patients in other subgroups too.
“The important message is that we have an immunotherapy treatment that works for all the patients in the second-line setting—whatever the PD-L1 status, and whatever the clinical characteristics—and it provides doctors and patients with a new strong therapeutic option,” Barlesi told the Audio Journal of Oncology.
ESMO officer Solange Peters MD PhD, Médecin Cheffe for Thoracic Malignancies at the Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne in Switzerland said the trial had brought clarification about the role of immunotherapy in lung cancer.
“What we knew from the other trials is that it’s better to give immunotherapy than docetaxel. In terms of survival [it is] very obviously better. This trial confirms that the higher PD-L1 is expressed the stronger is the benefit. But this trial clearly shows that patients without expression of PD-L1—the biomarker-negative population—still benefit from atezolizumab,” she said.
Barlesi said that the idea of using a PD-L1-directed drug arose because such “checkpoint inhibitors” work by cancelling one of the mechanisms cancer cells use to evade the immune system.
“The goal of this treatment is to allow the immune system to control and possibly eliminate cancer calls, so atezolizumab might be useful in a very large setting of different cancers,” said Barlesi.
The OAK study enrolled 1225 patients with previously-treated NSCLC and—after stratifying them according to PD-L1 status, number of prior chemotherapy regimens and histology—randomized them to intravenous atezolizumab (1200mg every three weeks) or docetaxel (75 mg/m2 every three weeks).
While the study was able to quantify the benefit from treatment with the PD-L1 checkpoint inhibitor in all patients the study was also designed to look at subgroups, with patients stratified according to their levels of PD-L1 expression.
Patients with more than one percent expression of the PD-L1 biomarker lived 52 percent longer if they received immunotherapy (15.7 months median compared with 10.3 months for docetaxel).
And patients in the highest group of PD-L1 expression treated with atezolizumab lived more than a year longer—to a median of 20.5 months as compared with 8.9 months for matched patients receiving docetaxel.
But even the patients who had no PD-L1 expression lived longer (12.6 as compared with 8.9 months median) with immunotherapy than with chemotherapy. And the improvements in overall survival were similar in patients with squamous and non-squamous histology.
Moderate to severe treatment-related adverse events occurred in 15 percent of patients treated with immunotherapy as compared with 43 percent of those receiving chemotherapy. There were no deaths related to atezolizumab and one death was related to docetaxel.
“Atezolizumab offers a new second-line therapeutic strategy for patients with non-small-cell lung cancer, regardless of the PD-L1 status of the tumor,” Barlesi said.
Martin Reck MD PhD, from the Department of Thoracic Oncology at Lung Clinic Grosshansdorf in Germany, commented that the OAK study had provided “a very important piece of information” on the role of PD-L1/PD-1 antibodies in treatment of NSCLC and that it confirmed the overall survival benefits shown in the earlier POPLAR and CHECKMATE trials.
But he said the results show that it would not be possible to use PD-L1 testing negativity as an exclusion factor for treatment since the drug benefited all subgroups.
“My suggestion would be that PD-L1 is perhaps one imperfect surrogate marker to describe the activity. It’s a good “enrichment” factor but we need additional markers for the characterization of patients who might not benefit from this treatment or who might really benefit.”
Stefan Zimmermann MD from Hôpital Fribourgeois, HFR Hôpital Cantonal, Fribourg, Switzerland, who chaired a briefing on the OAK findings at ESMO told the Audio Journal the new data on atezolizumab needed to be viewed in the context of other studies with other checkpoint inhibitors.
“It reinforces the message that in second and further lines of therapy there is benefit even in patients who have low or no expression of PD-L1,” he said, and his interpretation of the data was that “you don’t need an assay”, since most—if not all—subgroups benefit from an immune-oncology approach rather than standard chemotherapy.
“I can imagine that atezolizumab will get regulatory approval so we’ll now have a wealth of choices in second and further lines. We [already] have nivolumab that has regulatory approval, we have pembrolizumab in second line for PD-L1-espressing patients and we might [soon] have atezolizumab,” he said.
COPENAGEN—Adding the PD-1 (programmed cell death protein 1) antibody pembrolizumab to standard first-line chemotherapy with carboplatin and pemetrexed for previously-untreated patients with advanced non-squamous non-small-cell lung cancer (NSCLC) and good performance status significantly improved objective response rate (ORR) and progression-free survival (PFS) in the phase II KEYNOTE-021 study reported at the 2016 European Society for Medical Oncology (ESMO) Congress in Copenhagen. (Abstract LBA46_PR)
“Pembrolizumab enables T cells to reactivate and accomplish what they are designed to do—facilitate tumor cell killing,” said principal investigator Corey Langer MD FACP, Professor of Medicine and Director of Thoracic Oncology at the Abramson Cancer Center, University of Pennsylvania in Philadelphia PA, commenting on the findings with this “checkpoint inhibitor” immunotherapy.
Langer told the Audio Journal of Oncology the study showed a “statistically significant and clinically meaningful improvement for both response and progression-free survival for the combination.”
The KEYNOTE-021 study randomized 123 patients with stage IIIB or stage IV, NSCLC to receive four cycles of carboplatin and pemetrexed (500 mg/m2 every three weeks), with or without 24 months treatment with pembrolizumab (200mg every three weeks).
After a median follow-up of 10.6 months, there was a significantly greater objective response rate (55 percent) in the patients who received pembrolizumab in addition to chemotherapy, compared to those treated with chemotherapy alone (29 percent).
PD-L1 (programmed cell death-ligand 1) expression was not used to select patients for treatment with the immune checkpoint inhibitor, but the investigators found a higher response rate (around 80 percent) for the combination in tumors with PD-L1 over-expression, consistent with the known and licensed activity of the agent in patients with metastatic NSCLC tumors testing positive for this biomarker.
Progression free survival was longer for patients treated with the pembrolizumab combination (median 13.0 months) as compared with those receiving chemotherapy (8.9 months). More than 90 per cent of patients lived longer than six months but there was no difference in overall survival between the two arms.
There were more grade 3 or 4 adverse events with the pembrolizumab combination (39 percent) than with chemotherapy (26 percent), but Langer said toxicity was readily manageable and did not affect rates of treatment discontinuation or treatment-related deaths.
“So even though toxicity may be a little bit worse it’s not a show-stopper,” he said, adding that he was encouraged by the findings. “With the judicious use of immunotherapy I believe we are moving the bar forward for this population,” he said.
ESMO congress officer Solange Peters MD PhD, Head of Medical Oncology and Médecin Cheffe of Thoracic Malignancies at the Centre Hospitalier Universitaire Vaudois (CHUV) in Lausanne, Switzerland said the KEYNOTE-021 finding reinforced the idea that every single patient should be exposed to immunotherapy at some time.
“On present [evidence] this should be sequential,” she said. “But I would advise doctors to keep an eye on these data about combination chemo and immuno-[therapies]—not only in lung, but in other diseases too, because it might be of great interest in the future.”
Peters said it was worth continuing to investigate combinations of chemotherapy plus immunotherapy as first line therapy for NSCLC since any worries that chemotherapy might damage T-cells had been lessened with the arrival of the KEYNOTE data.
“This combination was almost doubling the response rate as compared to chemotherapy alone—and the PFS [was] influenced positively by the combination. So it means that this is not a regimen that will damage the T-cell,” she said.
But she emphasized that we do not presently know if the benefits giving the two treatments concurrently were likely to be superior—in the long run—to using the same agents sequentially. Data on overall survival and long-term follow up of the PFS were needed, she said. “So I think it’s a bit early to say [this is] going to be a standard because we need to see that long-term benefit.”
Commenting on the study, Raffaele Califano MD, Consultant in Medical Oncology at The Christie Hospital and University Hospital of South Manchester in Manchester, UK said: “Data for the combination of chemotherapy plus pembrolizumab in this population is certainly encouraging, and it is reassuring to see that the addition of pembrolizumab to first-line chemotherapy has a manageable toxicity profile and doesn’t increase the incidence of treatment-related adverse events or deaths.”
“Notably, the progression-free survival reported in the standard arm was much longer than expected and nearly doubled when compared to historical data,” Califano said. But he added that this could be due to patient selection or other clinical or molecular characteristics of the patients enrolled in this study.
“In order to establish if this strategy should be adopted in clinical practice, these results should be investigated further in a phase III randomized study with a similar design, adequately powered for progression-free survival and with robust assessment of patient’s reported outcomes,” he said.