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
Mené sur 165 patients atteints d'un mélanome et présentant des métastases cérébrales, cet essai de phase II évalue l'efficacité, du point de vue du taux de bénéfice clinique intracrânien, et la toxicité d'un traitement de première ligne combinant nivolumab et ipilimumab
Background : Combination nivolumab plus ipilimumab was efficacious in patients with asymptomaticmelanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patientswith 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 (0·5–3·0 cm in diameter). Asymptomatic patients (cohortA) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 andno neurological symptoms or baseline corticosteroid use; symptomatic patients (cohortB) had an ECOG performance status of 0–2 with stable neurological symptoms and couldbe receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg wasgiven intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every2 weeks for up to 2 years, until disease progression or unacceptable toxicity. Theprimary endpoint was intracranial clinical benefit rate (complete responses, partialresponses, 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 34·3 months[IQR 14·7–36·4]) and 18 were symptomatic (cohort B; median follow-up 7·5 months [1·2–35·2]).Investigator-assessed intracranial clinical benefit was observed in 58 (57·4% [95%CI 47·2–67·2]) of 101 patients in cohort A and three (16·7% [3·6–41·4]) of 18 patientsin cohort B; investigator-assessed objective response was observed in 54 (53·5% [43·3–63·5])patients in cohort A and three (16·7% [3·6–41·4]) patients in cohort B. 33 (33%) patientsin cohort A and three (17%) patients in cohort B had an investigator-assessed intracranialcomplete response. For patients in cohort A, 36-month intracranial progression-freesurvival was 54·1% (95% CI 42·7–64·1) and overall survival was 71·9% (61·8–79·8).For patients in cohort B, 36-month intracranial progression-free survival was 18·9%(95% CI 4·6–40·5) and overall survival was 36·6% (14·0–59·8). The most common grade3–4 treatment-related adverse events (TRAEs) were increased alanine aminotransferaseand aspartate aminotransferase (15 [15%] of 101 patients each) in cohort A; no grade3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 eventsoccurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, andincreased alanine aminotransferase (five [5%] of each among the 101 patients in cohortA); no serious TRAE occurred in more than one patient each in cohort B. There wasone treatment-related death (myocarditis in cohort A). Interpretation : The durable 3-year response, overall survival, and progression-free survival ratesfor asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomaticdisease in patients with MBM remains difficult to treat, but some patients achievea long-term response with the combination.