BACKGROUND: Approved systemic treatments for malignant pleural mesothelioma (MPM) were limited to chemotherapy regimens that have moderate survival benefit with poor outcomes. Nivolumab plus ipilimumab showed clinical benefit in other tumour types, including first-line non-small cell lung cancer. We hypothesised that this regimen would improve overall survival in MPM. METHODS:This open-label phase 3 study was conducted at 103 hospitals across 21 countries. Adults with previously untreated, histologically confirmed unresectable MPM were randomised (1:1) to nivolumab (3 mg/kg intravenously Q2W) plus ipilimumab (1 mg/kg intravenously Q6W) for ≤2 years, or platinum plus pemetrexed chemotherapy (pemetrexed [500 mg/m 2 intravenously] plus cisplatin [75 mg/m 2 intravenously] or carboplatin [AUC 5 mg/mL/min intravenously]) Q3W for up to 6 cycles. The primary endpoint was overall survival (all randomised patients); safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, NCT02899299. FINDINGS:Between November 29, 2016 and April 18, 2018, 713 patients were enrolled; 303 were randomised to nivolumab plus ipilimumab and 302 to chemotherapy. At the prespecified interim analysis (median follow-up 29•7 months [IQR,[26][27][28][29][30][31][32]), nivolumab plus ipilimumab significantly prolonged overall survival versus chemotherapy. Median overall survival was 18•1 months (95% CI 16•8-21•4) versus 14•1 months (95% CI 12•4-16•2), with a hazard ratio of 0•74 (96•6% CI 0•60-0•91; p=0•0020); 2year overall survival rates were 41% (95% CI 35•1-46•5) and 27% (95% CI 21•9-32•4), respectively.Grade 3-4 treatment-related adverse events were reported in 91 (30%) of 300 patients treated with nivolumab plus ipilimumab and 91 (32%) of 284 treated with chemotherapy. There were three (1%) and one (<1%) treatment-related deaths, respectively. INTERPRETATION:Nivolumab plus ipilimumab provided statistically significant and clinically meaningful improvements in overall survival versus standard-of-care chemotherapy, supporting the use of this first-in-class approved (United States) regimen for previously untreated unresectable MPM.

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