LBPO.MCB01 · 分子与细胞生物学 · Late-Breaking

Translational analyses from the randomized phase 3 DREAM3R trial: DuRvalumab with chEmotherapy as first line treAtment in advanced pleural Mesothelioma

编号 LB105 展板 13 时间 4/19 02:00–05:00 区域 Section 55 主讲 Valsamo (Elsa) Anagnostou, MD;PhD

分会场 Late-Breaking Research: Molecular/Cellular Biology and Genetics 1

该海报暂无可访问的完整资料 AACR 官方页面 ↗

作者与单位

Valsamo (Elsa) Anagnostou¹, Anna K. Nowak², Chris Brown³, Brett G. M. Hughes⁴, Noushin Niknafs¹, Tracy Hoang⁵, Jaime Wehr¹, Connull Leslie⁶, Qiong Meng¹, Asimina Zoitou¹, Kennet J. O’Byrne⁷, Wee L. Chin⁸, Thomas John⁹, Peter Illei¹, Sonia Yip¹⁰, Nick Pavlakis¹¹, Julie Brahmer¹, Martin R. Stockler¹⁰, Patrick M. Forde¹², Alistair Cook¹³

¹Johns Hopkins University, Baltimore, MD,²Medical School, University of Western Australia, WA, Australia,³NHMRC Clinical Trials Centre, University of Sydney, NSW, Australia,⁴The Prince Charles Hospital, Cancer Care Services, QLD, Australia,⁵Institute for Respiratory Health, University of Western Australia, WA, Australia,⁶PathWest Laboratory Medicine, Nedlands, WA, Australia,⁷Queensland University of Technology, Brisbane, Australia,⁸Sir Charles Gairdner Hospital, WA, Australia,⁹Peter MacCallum Cancer Centre, Vic, Australia, Victoria, Australia,¹⁰University of Sydney, NSW, Australia,¹¹Genesis Care, North Shore Health Hub, St Leonards, NSW, Australia,¹²Trinity St. James’s Cancer Institute, Trinity College, Dublin, Ireland,¹³School of Biomedical Sciences, University of Western Australia, Baltimore, MD

摘要 Abstract

Introduction: The phase 3 randomized DREAM3R clinical trial evaluated durvalumab + chemotherapy (D+Ch) compared to chemotherapy alone (Ch) for patients with pleural mesothelioma (PM) and showed an improvement in overall response rate (ORR) with D+Ch (Clinical trial identifier: NCT04334759). The study enrolment was terminated early due to slow accrual, and the primary endpoint of overall survival (OS) was not met. Here, we report translational analyses of genomic landscapes and PD-L1 expression and their association with clinical endpoints in the DREAM3R trial. Methods: Between February 2021 and November 2023, 173 participants with unresectable PM were randomized to D+Ch (n=113) vs Ch (n=60); most (94%) had epithelioid PM. Overall survival (OS) was the primary endpoint; secondary endpoints included progression-free survival (PFS) and objective response rate (ORR; by modified RECIST for PM). Pre-treatment tumor PD-L1 expression was evaluated by immunohistochemistry (pharmDx 22C3) in participants with available tissue. Tumor-positive score (TPS) was recorded, and PD-L1+ vs PD-L1- cohorts (≥1% vs <1%) were compared for OS, PFS, and ORR. Tumor mutational burden (TMB) estimates were derived by counting sequence alterations in coding regions using whole exome sequencing (n=91 in the D+Ch and n=35 in the Ch arm). Mutations were characterized by recurrence and functional consequence, and enrichment analyses were performed for individual mutations and for mutations that converged within gene families and cancer hallmarks. Genome-wide copy number profiles were used to derive tumor aneuploidy metrics and were intersected with sequence alterations to compute mutation clonality and the number of mutations in aneuploid regions. Results: Across the entire cohort, ORR among patients with PM expressing PD-L1 ≥1% vs <1% was 65% (31/48) vs 49% (45/92; Pearson's chi-squared p=0.077). PD-L1 expression or overall TMB was not associated with PFS or OS in the whole cohort or in the D+Ch and Ch subsets. Patients with tumors harboring a higher number of clonal multicopy mutations had longer OS (median survival 24.44 vs 17.61 months, p=0.0082). In the D+Ch arm, patients with PM who had a higher fraction of genome-wide loss of heterozygosity had a shorter OS (median survival 15.77 vs 24.57 months, p=0.0042). The effect of D+Ch vs Ch on PFS was more apparent among patients with tumors harboring inactivating BAP1 mutations (median survival 9.89 vs 6.21 months, p=0.064) and homozygous deletions in DNA damage repair genes (median survival 6.14 vs 5.75 months, p=0.069). Conversely, patients with LATS2 wild-type tumors attained longer PFS with D+Ch than with Ch alone (median survival 7.79 vs 5.9 months, p=0.027). Conclusions: Our findings suggest that durvalumab and chemotherapy warrant further investigation in biomarker-defined subsets of patients with unresectable PM.

利益披露 Disclosure

V. Anagnostou, Astra Zeneca ), Other, Advisory Board. Labcorp/Personal Genome Diagnostics ). Labcorp/Personal Genome Diagnostics Other, Consulting. Astra Zeneca Other, Consulting. Foundation Medicine Other, Honoraria. Roche Other, Honoraria. Guardant Health Other, Honoraria. Thermo Fisher Other, Consulting. Neogenomics Other, Advisory Board. A. K. Nowak, AstraZeneca ), Other, DSMB. Cancer council WA board Other, Non-Financial Interests, Personal, Member. Cancer Australia Advisory Council Other, Financial Interests, Personal, Advisory Board. International Mesothelioma Interest Group Other, Non-Financial Interests, Personal, International Mesothelioma Interest Group President Elect. C. Brown, None. B. G. M. Hughes, MSD Other, Financial Interests, Personal, Invited Speaker, Advisory Board. Bristol Myers Squibb Other, Financial Interests, Personal, Advisory Board. AstraZeneca Other, Financial Interests, Personal, Advisory Board. Roche Other, Financial Interests, Personal, Advisory Board. Pfizer Other, Financial Interests, Personal, Advisory Board. Regeneron Other, Financial Interests, Personal, Advisory Board. Sanofi Other, Financial Interests, Personal, Advisory Board. Eisai Other, Financial Interests, Personal, Advisory Board. Amgen Other, Financial Interests, Personal, Advisory Board. N. Niknafs, None.. T. Hoang, None.. J. Wehr, None.. C. Leslie, None.. Q. Meng, None.. A. Zoitou, None. K. J. O’Byrne, daiichi snaky Other, Financial Interests, Personal, Advisory Board, Advisory board meetings 2024. Astellas Other, Financial Interests, Personal, Invited Speaker. Merck Other, Financial Interests, Personal, Invited Speaker. Bayer Other, Financial Interests, Personal, Sponsorship for travel, accommodation and registration for ESMO Congress, Paris, 2022. BeiGene Other, Financial Interests, Personal, Other, Advice on drug development program, advisory board work and invited speaker. Bristol Meyers Squibb Other, Financial Interests, Personal, Other, Invited speaker; advisory board. Ipsen Other, Financial Interests, Personal, Advisory Board, Advice on development of cabozantinib. J&J Other, Financial Interests, Personal, Advisory board and invited speaker. Takeda Pharmaceuticals Other, Financial Interests, Personal, Advisory board and invited speaker. MSD Other, Financial Interests, Personal, Advisory board; invited speaker. Pfizer Other, Financial Interests, Personal, Advisory board work and invited speake. Roche – Genentech Other, Financial Interests, Personal, Advisory board; invited speaker. Sanofi Other, Financial Interests, Personal, Sponsorship to ESMO annual congress 2023 - flights, registration and accommodation. TriStar Other, Financial Interests, Personal, Advisor/consultant on project development by the company. Yuhan Other, Financial Interests, Personal, Advisory Board, Advice on development of Lasertinib. Boehringer-Ingelheim Other, Financial Interests, Personal, Advisory board and previous committee member for the LUX-lung program. Carpe Vitae Pharmaceuticals Pty Ltd g., Board of Directors, non-salaried role), Stock, Financial Interests, Personal, Co-founder. RGT diagnostics Other, Financial Interests, Personal, Start-up diagnostics focused on genomics. W. L. Chin, None. T. John, AstraZeneca Other, Financial Interests, Personal, Invited Speaker, Speaker tour Vietnam. BMS Other, Financial Interests, Personal, Advisory Board. AstraZeneca Other, Financial Interests, Personal, Advisory Board. Bayer Other, Financial Interests, Personal, Advisory Board. Specialised Therapeutics Other, Financial Interests, Personal, Advisory Board. Roche ), Other, Financial Interests, Advisory Board. Novartis ), Other, Financial Interests, Advisory Board. Pfizer ), Financial Interests, Advisory Board. Amgen ), Financial Interests, Advisory Board. Takeda ), Financial Interests, Advisory Board. PharmaMar ), Financial Interests, Advisory Board. Johnson and Johnson ), Financial Interests, Advisory Board. Seagen Pharmaceuticals ), Financial Interests, Advisory Board. Merck Seron ), Financial Interests, Advisory Board. Bayer ), Financial Interests, Advisory Board. BeiGene ), Financial Interests, Invited Speaker. AstraZeneca Other, Non-Financial Interests, Principal Investigator, Oceanic study. P. Illei, Bristol Myers-Squib ). AstraZeneca Other, Financial Interests, Personal, Advisory Board. AbbVie Other, Financial Interests, Personal, Advisory Board. Sanofi Other, Financial Interests, Personal, Advisory Board. Boehringer Ingelheim Other, Financial Interests, Personal, Advisory Board. Roche Other, Financial Interests, Personal, Advisory Board. Abbvie Other, Financial Interests, Personal, Education consulting. S. Yip, Lisata Therapeutics ), Other, Financial Interests, Research Grant. Bayer ), Financial Interests, Research Grant. N. Pavlakis, Boehringer Ingelheim Other, Financial Interests, Personal, Advisory Board. MSD Other, Financial Interests, Personal, Advisory Board. Merck KgA Other, Financial Interests, Personal, Advisory Board. BMS Other, Financial Interests, Personal, Advisory Board. AstraZeneca Other, Financial Interests, Personal, Advisory Board. Takeda Other, Financial Interests, Personal, Advisory Board. Pfizer ), Other, Financial Interests, Personal, Advisory Board, Trial Chair. Roche ), Other, Financial Interests, Personal, Advisory Board, Trial Chair. Amgen Other, Financial Interests, Personal, Advisory Board. BeiGene Other, Financial Interests, Personal, Advisory Board. Gilead Other, Financial Interests, Personal, Advisory Board. Zymeworks Other, Financial Interests, Personal, Advisory Board. BioNtech Other, Financial Interests, Personal, Advisory Board. Daiichi Sankyo Other, Financial Interests, Personal, Advisory Board. DUO Oncology Other, Financial Interests, Personal, Advisory Board. Johnson and Johnson Other, Financial Interests, Personal, Advisory Board. Bayer ), Other, Financial Interests, Trial Chair. J. Brahmer, AstraZeneca ), Other, Financial Interests, Personal, Advisory Board. Amgen Other, Financial Interests, Personal, Advisory Board. Bristol Myers Squibb International Other, Financial Interests, Personal, Advisory Board. summit therapeutics Other, Financial Interests, Personal, Advisory Board. Merck Other, Financial Interests, Personal, Advisory Board. GSK Other, Financial Interests, Personal, Advisory Board. NCCN Other, Non-Financial Interests, Leadership Role, Immunotherapy TOxicity Guideline CoChair. ASCO Other, Non-Financial Interests, Member. AACR Other, Non-Financial Interests, Member. SITC Other, Non-Financial Interests, Leadership Role, Guideline Co chair. ECOG-ACRIN Other, Non-Financial Interests, Leadership Role, Thoracic Cancer Committee Chair. M. R. Stockler, Bayer ), Other, Financial Interests, DASL. Astellas ), Other, Financial Interests. Amgen ), Other, c. MSD ), Other, Financial Interests. BMS ), Other, Financial Interests. Pfizer ), Other, Financial Interests. Roche ), Financial Interests. ADELE ), Other, Financial Interests. BeiGene ), Other, Financial Interests. NOVARTIS ), Other, Financial Interests. Tilray ), Other, Financial Interests. AstraZeneca ), Other, Financial Interests. P. M. Forde, Astra Zeneca Other, Financial Interests, Personal, Advisory Board, Advisory board member on drug development in lung cancer. BMS Other, Financial Interests, Personal, Advisory Board, Advisory board member on drug development in lung cancer. Genelux Other, Financial Interests, Personal, Advisory Board, Advisor on trial development. Regeneron Other, Financial Interests, Personal, Advisory Board, Advisory board member on lung cancer drug development. Teva Other, Financial Interests, Personal, Advisory Board, Advisory board lung cancer. J&J Other, Financial Interests, Personal, Advisory Board, Advisory board on lung cancer. Gilead Other, Financial Interests, Personal, Advisory Board, Advisory board on lung cancer. Daiichi Sankyo Other, Financial Interests, Personal, Advisory Board, Advisory board on lung cancer. AbbVie Other, Financial Interests, Personal, Advisory Board, Advisory board on early lung cancer. Chromacode Other, Financial Interests, Personal, Advisory Board, Advisory board on test development. Ascendis Other, Financial Interests, Personal, Advisory Board, lung cancer advisory board. Novocore Other, Financial Interests, Personal, Advisory Board. MSD Other, Financial Interests, Personal, Advisory Board, Lung cancer advisory board. AstraZeneca Other, Financial Interests, Institutional, Coordinating PI, NeoCOAST2 and LATIFY studies. LUNGevity Lung Cancer Foundation Other, Non-Financial Interests, Leadership Role, Scientific Advisory Board. ASCO Other, Non-Financial Interests, Member. AACR Other, Non-Financial Interests, Member. SITC Other, Non-Financial Interests, Member. A. Cook, None.

在会议检索中打开