LBPO.MCB01 · 分子与细胞生物学 · Late-Breaking

随机3期DREAM3R试验的转化研究分析：度伐利尤单抗联合化疗作为晚期胸膜间皮瘤一线治疗

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

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作者与单位 Authors & Affiliations

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

中文摘要

引言：3期随机DREAM3R临床试验评估了度伐利尤单抗+化疗（D+Ch）与单纯化疗（Ch）相比用于胸膜间皮瘤（PM）患者的疗效，结果显示D+Ch可提高总体缓解率（ORR）（临床试验标识号：NCT04334759）。该研究因入组缓慢而提前终止，未达到总生存期（OS）的主要终点。在此，我们报告DREAM3R试验中基因组图谱和PD-L1表达的转化研究分析及其与临床终点的关联。方法：在2021年2月至2023年11月期间，173名不可切除PM受试者被随机分配至D+Ch（n=113）与Ch（n=60）；大多数（94%）为上皮样PM。总生存期（OS）为主要终点；次要终点包括无进展生存期（PFS）和客观缓解率（ORR；采用PM改良RECIST标准）。对有可用组织的受试者，通过免疫组化（pharmDx 22C3）评估治疗前肿瘤PD-L1表达。记录肿瘤阳性评分（TPS），并比较PD-L1+与PD-L1-队列（≥1%与<1%）的OS、PFS和ORR。通过全外显子组测序计数编码区序列改变，得出肿瘤突变负荷（TMB）估计值（D+Ch组n=91，Ch组n=35）。突变按复发性和功能后果进行表征，并对个别突变以及在基因家族和癌症标志内汇聚的突变进行富集分析。全基因组拷贝数图谱用于得出肿瘤非整倍体指标，并与序列改变交叉分析，以计算突变克隆性和非整倍体区域中的突变数量。结果：在整个队列中，表达PD-L1≥1%与<1%的PM患者的ORR分别为65%（31/48）与49%（45/92；Pearson卡方检验p=0.077）。在整个队列以及D+Ch和Ch亚组中，PD-L1表达或总体TMB均与PFS或OS无关。携带较多克隆性多拷贝突变的肿瘤患者OS较长（中位生存期24.44对17.61个月，p=0.0082）。在D+Ch组中，全基因组杂合性缺失比例较高的PM患者OS较短（中位生存期15.77对24.57个月，p=0.0042）。在携带失活性BAP1突变（中位生存期9.89对6.21个月，p=0.064）和DNA损伤修复基因纯合缺失（中位生存期6.14对5.75个月，p=0.069）的肿瘤患者中，D+Ch相对于Ch对PFS的效应更为明显。相反，LATS2野生型肿瘤患者使用D+Ch比单用Ch获得更长的PFS（中位生存期7.79对5.9个月，p=0.027）。结论：我们的发现提示，度伐利尤单抗联合化疗值得在生物标志物定义的不可切除PM患者亚组中进一步研究。

查看英文原文 English 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.

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