Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study

Background Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial. Methods This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged >= 18 years) with measurable MBM (0middot5-3middot0 cm in diameter). Asymptomatic patients (cohort A) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no neurological symptoms or baseline corticosteroid use; symptomatic patients (cohort B) had an ECOG performance status of 0-2 with stable neurological symptoms and could be receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg was given intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity. The primary endpoint was intracranial clinical benefit rate (complete responses, partial responses, or stable disease lasting >= 6 months) assessed in all treated patients. Intracranial progression-free survival and overall survival were key secondary endpoints. This study is registered with ClinicalTrials.gov, NCT02320058. Findings Between Feb 19, 2015, and Nov 1, 2017, 119 (72%) of 165 screened patients were enrolled and treated: 101 patients were asymptomatic (cohort A; median follow-up 34middot3 months [IQR 14middot7-36middot4]) and 18 were symptomatic (cohort B; median follow-up 7middot5 months [1middot2-35middot2]). Investigator-assessed intracranial clinical benefit was observed in 58 (57middot4% [95% CI 47middot2-67middot2]) of 101 patients in cohort A and three (16middot7% [3middot6-41middot4]) of 18 patients in cohort B; investigator-assessed objective response was observed in 54 (53middot5% [43middot3-63middot5]) patients in cohort A and three (16middot7% [3middot6-41middot4]) patients in cohort B. 33 (33%) patients in cohort A and three (17%) patients in cohort B had an investigator assessed intracranial complete response. For patients in cohort A, 36-month intracranial progression-free survival was 54middot1% (95% CI 42middot7-64middot1) and overall survival was 71middot9% (61middot8-79middot8). For patients in cohort B, 36-month intracranial progression-free survival was 18middot9% (95% CI 4middot6-40middot5) and overall survival was 36middot6% (14middot0-59middot8). The most common grade 3-4 treatment-related adverse events (TRAEs) were increased alanine aminotransferase and aspartate aminotransferase (15 [15%] of 101 patients each) in cohort A; no grade 3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 events occurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, and increased alanine aminotransferase (five [5%] of each among the 101 patients in cohort A); no serious TRAE occurred in more than one patient each in cohort B. There was one treatment-related death (myocarditis in cohort A). Interpretation The durable 3-year response, overall survival, and progression-free survival rates for asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomatic disease in patients with MBM remains difficult to treat, but some patients achieve a long-term response with the combination. Funding Bristol Myers Squibb. Copyright (c) 2021 Elsevier Ltd. All rights reserved.

Automated summary

The study demonstrated the durable response, overall survival, and progression-free survival rates for asymptomatic patients treated with nivolumab plus ipilimumab. In contrast, the efficacy was lower in symptomatic patients. Treatment-related adverse events were mainly mild to moderate.