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. Citation Format: Valsamo (Elsa) Anagnostou, Anna K. Nowak, Chris Brown, Brett G. Hughes, Noushin Niknafs, Tracy Hoang, Jaime Wehr, Connull Leslie, Qiong Meng, Asimina Zoitou, Kennet J. O’Byrne, Wee L. Chin, Thomas John, Peter Illei, Sonia Yip, Nick Pavlakis, Julie Brahmer, Martin R. Stockler, Patrick M. Forde, Alistair Cook. Translational analyses from the randomized phase 3 DREAM3R trial: DuRvalumab with chEmotherapy as first line treAtment in advanced pleural Mesothelioma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB105.
Anagnostou et al. (Fri,) studied this question.