Durvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial

• Type of Material: Article
• Authors: Patrick M Forde, Johns Hopkins University; Valsamo Anagnostou, Johns Hopkins University; Zhuoxin Sun, ECOG-ACRIN Biostatistics Center; Suzanne E Dahlberg, Boston Childrens Hospital; Hedy L Kindler, Univ Chicago Med; Noushin Niknafs, Johns Hopkins University; Thomas Purcell, University of Washington; Rafael Santana-Davila, University of Washington; Arkadius Z Dudek, Metrominnesota Community Oncol Res Consortium; Hossein Borghaei, Fox Chase Cancer Center; Mara Lanis, Johns Hopkins University; Zineb Belcaid, Johns Hopkins University; Kellie N Smith, Johns Hopkins University; Archana Balan, Johns Hopkins University; James R White, Johns Hopkins University; Christopher Cherry, Johns Hopkins University; Ashok I.K Sivakumar, Johns Hopkins University; Xiaoshan M Shao, Johns Hopkins University; Hok Y Chan, Johns Hopkins University; Dipika Singh, Johns Hopkins University; Sampriti Thapa, Johns Hopkins University; Peter B Illei, Johns Hopkins University; Drew M Pardoll, Johns Hopkins University; Rachel Karchin, Johns Hopkins University; Victor E Velculescu, Johns Hopkins University; Julie R Brahmer, Johns Hopkins University; Suresh Ramalingam, Emory University
• Language: English
• Date: 2021-11-08
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41591-021-01541-0
• Title of Journal or Parent Work: NATURE MEDICINE
• Volume: 27
• Issue: 11
• Start Page: 1910
• End Page: +
• Grant/Funding Information: The PrE0505 clinical trial was sponsored by AstraZeneca and PrECOG. This work was supported, in part, by Johns Hopkins SKCCC core grant NCI CCSG P30 CA006973, Department of Defense Congressionally Directed Medical Research Programs grant CA190755 (V.A. and P.M.F.), National Institutes of Health grants CA121113 (V.A. and V.V.), CA006973 (V.V.) and R37CA251447 (K.N.S.), ECOG-ACRIN Thoracic Malignancies Integrated Translational Science Center grant UG1CA233259 (V.A., V.V., Z.S. and S.R.), the Bloomberg-Kimmel Institute for Cancer Immunotherapy (V.A, P.M.F. and K.N.S.), the V Foundation (V.A. and V.V.), the IASLC Foundation (K.N.S), the Lung Cancer Foundation of America (K.N.S.), Swim Across America (V.A. and K.N.S.), the Florence Lomax Eley Fund (V.A., P.M.F. and J.B.) and the LUNGevity Foundation (V.A., V.V. and K.N.S.).
• Keywords: CISPLATIN; ASBESTOS; Cell Biology; MULTICENTER; OPEN-LABEL; Biochemistry & Molecular Biology; Science & Technology; GERMLINE BAP1 MUTATIONS; Medicine, Research & Experimental; SAFETY; TUMOR; CLASS-I; IMMUNE CHECKPOINT BLOCKADE; SOMATIC MUTATIONS; Life Sciences & Biomedicine; Research & Experimental Medicine
• Research Categories: Health Sciences, Pathology; Health Sciences, Oncology; Engineering, Biomedical

Abstract

Mesothelioma is a rare and fatal cancer with limited therapeutic options until the recent approval of combination immune checkpoint blockade. Here we report the results of the phase 2 PrE0505 trial (NCT02899195) of the anti-PD-L1 antibody durvalumab plus platinum-pemetrexed chemotherapy for 55 patients with previously untreated, unresectable pleural mesothelioma. The primary endpoint was overall survival compared to historical control with cisplatin and pemetrexed chemotherapy; secondary and exploratory endpoints included safety, progression-free survival and biomarkers of response. The combination of durvalumab with chemotherapy met the pre-specified primary endpoint, reaching a median survival of 20.4 months versus 12.1 months with historical control. Treatment-emergent adverse events were consistent with known side effects of chemotherapy, and all adverse events due to immunotherapy were grade 2 or lower. Integrated genomic and immune cell repertoire analyses revealed that a higher immunogenic mutation burden coupled with a more diverse T cell repertoire was linked to favorable clinical outcome. Structural genome-wide analyses showed a higher degree of genomic instability in responding tumors of epithelioid histology. Patients with germline alterations in cancer predisposing genes, especially those involved in DNA repair, were more likely to achieve long-term survival. Our findings indicate that concurrent durvalumab with platinum-based chemotherapy has promising clinical activity and that responses are driven by the complex genomic background of malignant pleural mesothelioma.