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

Summary

Background

Approved systemic treatments for malignant pleural mesothelioma (MPM) have been limited to chemotherapy regimens that have moderate survival benefit with poor outcomes. Nivolumab plus ipilimumab has shown 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, randomised, phase 3 study (CheckMate 743) was run at 103 hospitals across 21 countries. Eligible individuals were aged 18 years and older, with previously untreated, histologically confirmed unresectable MPM, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to nivolumab (3 mg/kg intravenously once every 2 weeks) plus ipilimumab (1 mg/kg intravenously once every 6 weeks) for up to 2 years, or platinum plus pemetrexed chemotherapy (pemetrexed [500 mg/m² intravenously] plus cisplatin [75 mg/m² intravenously] or carboplatin [area under the concentration-time curve 5 mg/mL per min intravenously]) once every 3 weeks for up to six cycles. The primary endpoint was overall survival among all participants randomly assigned to treatment, and safety was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02899299, and is closed to accrual.

Findings

Between Nov 29, 2016, and April 28, 2018, 713 patients were enrolled, of whom 605 were randomly assigned to either nivolumab plus ipilimumab (n=303) or chemotherapy (n=302). 467 (77%) of 605 participants were male and median age was 69 years (IQR 64–75). At the prespecified interim analysis (database lock April 3, 2020; median follow-up of 29·7 months [IQR 26·7–32·9]), nivolumab plus ipilimumab significantly extended overall survival versus chemotherapy (median overall survival 18·1 months [95% CI 16·8–21·4] vs 14·1 months [12·4–16·2]; hazard ratio 0·74 [96·6% CI 0·60–0·91]; p=0·0020). 2-year overall survival rates were 41% (95% CI 35·1–46·5) in the nivolumab plus ipilimumab group and 27% (21·9–32·4) in the chemotherapy group. 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. Three (1%) treatment-related deaths occurred in the nivolumab plus ipilimumab group (pneumonitis, encephalitis, and heart failure) and one (<1%) in the chemotherapy group (myelosuppression).

Interpretation

Nivolumab plus ipilimumab provided significant and clinically meaningful improvements in overall survival versus standard-of-care chemotherapy, supporting the use of this first-in-class regimen that has been approved in the USA as of October, 2020, for previously untreated unresectable MPM.

Funding

Bristol Myers Squibb.

Introduction

Malignant pleural mesothelioma (MPM) is a highly aggressive cancer and typically unresectable at diagnosis, with less than 10% of patients surviving 5 years or beyond.1, 2 Historically, age, sex, tumour grade and stage, and histology have been shown to be independent prognostic factors. Notably, worse prognosis has been reported for non-epithelioid histology versus the epithelioid subtype.1, 2, 3 Until October, 2020, platinum agents plus folate antimetabolites, such as pemetrexed, have been the only approved first-line treatment regimens for MPM since 2004.4, 5 However, long-term survival outcomes remain poor with chemotherapy;6, 7, 8, 9 bevacizumab has been added to these regimens¹⁰ but its use varies across regions. As such, there is an urgent need for new and effective therapeutic options.

Nivolumab, a fully human anti-programmed cell death 1 (PD-1) antibody, and ipilimumab, a fully human anti-cytotoxic T-lymphocyte 4 (CTLA-4) antibody are immune checkpoint inhibitors with distinct but complementary mechanisms of action. Ipilimumab induces T-cell proliferation and de-novo anti-tumour T-cell responses, including in memory T cells, whereas nivolumab restores the function of existing anti-tumour T cells.¹¹ Nivolumab plus ipilimumab is approved in various tumours¹² and has shown durable overall survival benefit in melanoma,¹³ renal cell carcinoma,¹⁴ and in non-small-cell lung cancer (NSCLC).¹⁵ Furthermore, National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN guidelines) recommend nivolumab with or without ipilimumab as a preferred treatment option (category 2A) in second-line or later MPM settings based on results from three phase 2 trials,16, 17, 18 including the multicentre, open-label, randomised, non-comparative IFCT-1501 MAPS2 trial that showed encouraging clinical activity of the combination therapy.¹⁶

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.

CheckMate 743 is a phase 3 study designed to assess efficacy and safety of first-line nivolumab plus ipilimumab versus platinum plus pemetrexed chemotherapy in unresectable MPM. Here we present results from the prespecified interim analysis, which has led to nivolumab plus ipilimumab gaining approval in the USA.¹² Additionally, NCCN guidelines recommend nivolumab plus ipilimumab as a preferred first-line option (category 2A) for patients with biphasic or sarcomatoid histology and is also an option for those with epithelioid histology.