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Here we report the results of the phase 2 PrE0505 trial (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02899195\">NCT02899195<\/jats:ext-link>) 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.<\/jats:p>","DOI":"10.1038\/s41591-021-01541-0","type":"journal-article","created":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T17:19:00Z","timestamp":1636391940000},"page":"1910-1920","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":120,"title":["Durvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial"],"prefix":"10.1038","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6925-6344","authenticated-orcid":false,"given":"Patrick M.","family":"Forde","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9480-3047","authenticated-orcid":false,"given":"Valsamo","family":"Anagnostou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoxin","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne E.","family":"Dahlberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hedy L.","family":"Kindler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noushin","family":"Niknafs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Purcell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Santana-Davila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arkadiusz Z.","family":"Dudek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hossein","family":"Borghaei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"Lanis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zineb","family":"Belcaid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kellie N.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Archana","family":"Balan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James R.","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Cherry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I. 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P.M.F. has received research funding to his institution from AstraZeneca, Bristol Myers Squibb, Novartis, Corvus and Kyowa. He has also served as a consultant for Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Iteos, Janssen, Mirati, Novartis and Sanofi and as a data and safety monitoring board member for Polaris and Flame Therapeutics. A.D. is Chief Medical Officer and Chief Executive Officer at TTC Oncology, Chief Medical Officer at Luminary Therapeutics, Chief Medical Officer at IGF Oncology, Chief Medical Officer at Squarex and an advisor to the Martell Diagnostic Laboratory. K.N.S. receives research funding to her institution from Bristol Myers Squibb, AstraZeneca and Enara Bio and holds founder\u2019s equity in ManaT Bio. V.E.V. is a founder of Delfi Diagnostics and Personal Genome Diagnostics, serves on the board of directors and as a consultant for both organizations and owns Delfi Diagnostics and Personal Genome Diagnostics stock, which are subject to certain restrictions under university policy. Additionally, Johns Hopkins University owns equity in Delfi Diagnostics and Personal Genome Diagnostics. V.E.V. is an inventor of multiple licensed patents related to technologies from Johns Hopkins University. Some of these licenses and relationships are associated with equity or royalty payments directly to Johns Hopkins and V.E.V. V.E.V. is an advisor to Bristol Myers Squibb, Danaher, Genentech and Takeda Pharmaceuticals. Within the last 5 years, V.E.V. has been an advisor to Merck and Ignyta. These arrangements have been reviewed and approved by Johns Hopkins University in accordance with its conflict of interest policies. D.P. is a consultant for Aduro Biotech, Amgen, Bayer, Dynavax, Enara, FLX Bio, Immunomic Therapeutics, Janssen, Merck, Rock Springs Capitol, Tizona and Trieza; is on the Board of Directors of DNAtrix; is on the scientific advisory board of Immununica, WindMil, Dracen, Camden Partners and Astellas; receives research support from Bristol Myers Squibb and Compugen; and is a founder of ManaT Bio. C.C. is the founder of CM Cherry Consulting. J.W. is a consultant for Personal Genome Diagnostics, is the founder and owner of Resphera Biosciences and holds patents, royalties or other intellectual property from Personal Genomic Diagnostics. R.S.-D. is a consultant for Genentech\/Roche, Bayer, Bristol Myers Squibb, Eli Lilly, AstraZeneca, NGM Biopharmaceuticals and Takeda Science Foundation. H.B. receives research support from Millennium, Merck, Celgene, Bristol Myers Squibb and Eli Lilly; is on the advisory board and\/or a consultant for Bristol Myers Squibb, Eli Lilly, Genentech, Celgene, Pfizer, Merck, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, Novartis, Genmab, Regeneron, BioNTech, Cantargia AB, Amgen, Abbvie, Axiom, PharmaMar, Takeda, Huya Bio, Mirati and Daiichi Sankyo; is on the data and safety monitoring board of the University of Pennsylvania, CAR T Program, Takeda and Incyte; is on the scientific advisory board for Sonnetbio (stock options), Rgenix (stock options) and Nucleai (stock options); receives honoraria from Amgen, Pfizer and Daiichi Sankyo; and receives travel support from Amgen, Bristol Myers Squibb, Merck, Eli Lilly, EMD-Serono and Genentech. J.B. is on the advisory board and\/or a consultant for Amgen, AstraZeneca, Bristol Myers Squibb, Genentech\/Roche, Eli Lilly, GlaxoSmithKline, Merck, Sanofi and Regeneron; receives grant research funding from AstraZeneca, Bristol Myers Squibb, Genentech\/Roche, Merck, RAPT Therapeutics and Revolution Medicines; and is on the data and safety monitoring board\/committees of GlaxoSmithKline, Sanofi and Janssen. H.L.K. reports personal fees from Aldeyra Therapeutics, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Kyowa, Merck, Paredox Therapeutics, Deciphera, Inhibrx and Inventiva; and non-financial support from AstraZeneca, Boehringer-Ingelheim, Merck, Paredox Therapeutics and Inventiva. H.L.K. also reports funds given to support clinical trials at her institution from Aduro, AstraZeneca, Bayer, Bristol Myers Squibb, Deciphera, GlaxoSmithKline, Eli Lilly, Merck, Polaris, Verastem, Blueprint, Tesaro and Inhibrx. S.R. is a consultant for Amgen, Bristol Myers Squibb, Genentech\/Roche, Merck, AstraZeneca, Takeda, Eisai, Daiichi Sankyo, Sanofi, GlaxoSmithKline and Eli Lilly and receives grants from Tesaro, Merck, AstraZeneca, Advaxis, Bristol Myers Squibb, Amgen, Takeda, Genmab and GlaxoSmithKline. All other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}