First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial
Mené dans 21 pays sur 605 hommes atteints d'un mésothéliome pleural malin non résécable (âge médian : 69 ans), cet essai de phase III évalue l'efficacité, du point de vue de la survie globale, et la toxicité d'un traitement de première ligne combinant nivolumab et ipilimumab (durée médiane de suivi : 29,7 ans)
Background : Approved systemic treatments for malignant pleural mesothelioma (MPM) have been limitedto chemotherapy regimens that have moderate survival benefit with poor outcomes. Nivolumab plus ipilimumab has shown clinical benefit in other tumour types, including first-linenon-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 previouslyuntreated, histologically confirmed unresectable MPM, and an Eastern Cooperative OncologyGroup 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 intravenouslyonce every 6 weeks) for up to 2 years, or platinum plus pemetrexed chemotherapy (pemetrexed[500 mg/m 2 intravenously] plus cisplatin [75 mg/m 2 intravenously] or carboplatin [area under the concentration-time curve 5 mg/mL permin intravenously]) once every 3 weeks for up to six cycles. The primary endpointwas overall survival among all participants randomly assigned to treatment, and safetywas 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 (IQR64–75). 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 significantlyextended 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-yearoverall survival rates were 41% (95% CI 35·1–46·5) in the nivolumab plus ipilimumabgroup and 27% (21·9–32·4) in the chemotherapy group. Grade 3–4 treatment-related adverseevents were reported in 91 (30%) of 300 patients treated with nivolumab plus ipilimumaband 91 (32%) of 284 treated with chemotherapy. Three (1%) treatment-related deathsoccurred in the nivolumab plus ipilimumab group (pneumonitis, encephalitis, and heartfailure) and one (<1%) in the chemotherapy group (myelosuppression). Interpretation : Nivolumab plus ipilimumab provided significant and clinically meaningful improvementsin overall survival versus standard-of-care chemotherapy, supporting the use of thisfirst-in-class regimen that has been approved in the USA as of October, 2020, forpreviously untreated unresectable MPM.
The Lancet 2021