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.

Summary Lung cancer, the leading cause of cancer mortality, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Single-cell RNA sequencing (scRNA-seq) of metastatic lung cancer was performed using 49 clinical biopsies obtained from 30 patients before and during targeted therapy. Over 20,000 cancer and tumor microenvironment (TME) single-cell profiles exposed a rich and dynamic tumor ecosystem. scRNA-seq of cancer cells illuminated targetable oncogenes beyond those detected clinically. Cancer cells surviving therapy as residual disease (RD) expressed an alveolar-regenerative cell signature suggesting a therapy-induced primitive cell-state transition, whereas those present at on-therapy progressive disease (PD) upregulated kynurenine, plasminogen, and gap-junction pathways. Active T-lymphocytes and decreased macrophages were present at RD and immunosuppressive cell states characterized PD. Biological features revealed by scRNA-seq were biomarkers of clinical outcomes in independent cohorts. This study highlights how therapy-induced adaptation of the multi-cellular ecosystem of metastatic cancer shapes clinical outcomes.

OverviewLung cancer is the leading cause of cancer-related death in the United States. An estimated 219,440 new cases (116,090 men; 103,350 women) of lung and bronchus cancer were diagnosed in 2009, and 159,390 deaths (88,900 men; 70,490 women) occurred from the disease.1 Only 15% of all lung cancer patients are alive 5 years or more after diagnosis

Purpose To provide evidence-based recommendations to practicing physicians and others on the management of malignant pleural mesothelioma. Methods ASCO convened an Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary, pathology, imaging, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 1990 through 2017. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. Results The literature search identified 222 relevant studies to inform the evidence base for this guideline. Recommendations Evidence-based recommendations were developed for diagnosis, staging, chemotherapy, surgical cytoreduction, radiation therapy, and multimodality therapy in patients with malignant pleural mesothelioma. Additional information is available at www.asco.org/thoracic-cancer-guidelines and www.asco.org/guidelineswiki .