Research in context
Evidence before this study
We searched PubMed and abstracts from major oncology congresses for studies published from database inception until Oct 2, 2020, relevant to unresectable malignant pleural mesothelioma (MPM) and cancer immunotherapy regimens, with a focus primarily on first-line phase 3 trials, using search terms that included, but were not limited to (“mesothelioma” AND “nivolumab”) OR “chemotherapy” OR “pembrolizumab” OR “atezolizumab” OR “avelumab” OR “durvalumab” OR “ipilimumab” OR “tremelimumab” OR “PD-1” OR “PD-L1” OR “CTLA-4” (full names and abbreviations). Although we identified several studies assessing immunotherapy in MPM, we found no published randomised phase 3 studies investigating the efficacy or safety of immunotherapy regimens in the first-line setting. Various phase 1 and 2 studies in previously treated patients with MPM have suggested that immunotherapy regimens might provide clinical benefit. Notably, the multicentre, open-label, single-arm, phase 2 MERIT study led to the approval of nivolumab monotherapy for unresectable recurrent MPM in Japan. However, with recommended first-line systemic treatments limited to chemotherapy since 2004, with or without bevacizumab, there remains a need for new and effective therapeutic options. In the single-arm phase 2 DREAM study, first-line durvalumab plus chemotherapy exhibited promising activity in 54 patients with MPM, but the combination requires evaluation in a larger, randomised, phase 3 study. CheckMate 743 was designed to investigate the efficacy and safety of nivolumab plus ipilimumab versus chemotherapy. A previous non-comparative phase 2 trial (MAPS2) and single-arm phase 2 study (INITIATE) assessing nivolumab plus ipilimumab in MPM showed that this regimen was tolerable and exhibited encouraging clinical activity.
Added value of this study
Here we provide results from the randomised CheckMate 743 study, which is the first phase 3 study to show significant and clinically meaningful improvements in overall survival with immunotherapy versus standard-of-care platinum plus pemetrexed chemotherapy for first-line treatment of unresectable MPM. This regimen was found to show clinical benefit and tolerability, thus providing patients with a new first-line chemotherapy-free treatment option. Notably, survival with nivolumab plus ipilimumab was similar in patients with both non-epithelioid and epithelioid histologies, suggesting that the regimen could be considered for all patients with unresectable MPM. Responses were durable, with a 2-year duration of response rate of 32% of immunotherapy-treated patients. The safety profile of nivolumab plus ipilimumab was consistent with that observed in first-line non-small-cell lung cancer at this dose and schedule and no new safety signals were reported.
Implications of all the available evidence
Nivolumab plus ipilimumab can provide notable and clinically meaningful improvements in overall survival versus the current standard of care. Data from CheckMate 743 support a favourable clinical benefit–risk profile for nivolumab plus ipilimumab. Nivolumab plus ipilimumab is now indicated in the USA and Brazil as a first-line treatment for unresectable MPM.