First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial

Abstract

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.

P14/ARF-Positive Malignant Pleural Mesothelioma: A Phenotype With Distinct Immune Microenvironment

“…Recently, the use of immune checkpoint inhibitor (ICI) as single agents or in combination in previously treated and naïve patients has been shown to potentially prolong MPM patient survival even if the value of single agent checkpoint inhibitors is rather limited yielding overall response rates with immunotherapy around 30% (31). Even if more recently the Checkmate-743 study demonstrated a significant improvement in overall survival for the combination of nivolumab and ipilimumab (32), some issues about the expected response and the acceptable toxicity need to be addressed. While the clinical efficacy of ICI has been claimed to correlate with a high tumor mutational burden as in melanoma or NSCLC patients, mesothelioma has consistently been demonstrated to harbor a low mutation burden (10).…”

Digital Gene Expression Analysis of Epithelioid and Sarcomatoid Mesothelioma Reveals Differences in Immunogenicity

“…In a recent study, Horn et al demonstrated improved immune response and prognostically favorable TME remodeling of breast and lung cancer in a murine model after simultaneous inhibition of the CXCR1/2 and TGF-ß pathway during PDL-1 therapy [112]. As PDL-1 treatment in combination with a cisplatin-pemetrexed based chemotherapy [4,113] has yielded relatively promising results in MPM therapy so far, and with us showing increased activation of the corresponding pathways, transferring this experimental approach to the MPM might be important for future multimodal treatment.…”

“…This malignancy originates from the pleural mesothelium and is associated with a bad prognosis. Median survival times range from 14-20 months after initial diagnosis [3][4][5]. Generally, MPM can be differentiated into three major histologic subtypes, epithelioid (EMM), sarcomatoid (SMM), and biphasic (BMM).…”

“…Single agents (pembrolizumab, a PD-1 inhibitor) have shown increased response rates; however, they have failed to show benefits for progression-free (PFS) or overall survival (OS) [17]. Despite this setback, the Checkmate 743 study revealed a four-month OS benefit (mOS, HR: 0.74, CI: 0.60-0.91, p-value: 0.0020) and increased two-year survival rate (41% vs. 27%), when comparing immune checkpoint doublet therapy (ipilimumab and nivolumab) with standard systematic chemotherapy [4]. Nonetheless, responses remain unsatisfying with only marginal improvements compared to the best supportive care [18].…”

BAP1-Altered Malignant Pleural Mesothelioma: Outcomes With Chemotherapy, Immune Check-Point Inhibitors and Poly(ADP-Ribose) Polymerase Inhibitors

“…Numerically better results have been demonstrated with the combination of a PD-1/PD-L1 inhibitor with a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor (ORR of 25%, mPFS of 5.6-5.7 months, mOS of 16-16.6 months) (18,19). Recently, the combination of nivolumab, a PD-1-inhibitor, with ipilimumab, a CTLA-4 inhibitor, in treatment-naïve MPM, resulted in better OS as compared to therapy with platinum/pemetrexed (20). BRCA1 associated protein-1 (BAP1) is responsible for deubiquitination of histones and, as a result, protein transcription and cell cycle regulation (21), it also acts as a homologous recombination deoxyribonucleic acid (DNA) repair component found in the BRCA1/BARD1 complex (22).…”