Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

Abstract

Background: Nivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial.

Methods: We randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group versus the ipilimumab group.

Results: At a minimum follow-up of 36 months, the median overall survival had not been reached in the nivolumab-plus-ipilimumab group and was 37.6 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P<0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P<0.001]). The overall survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The safety profile was unchanged from the initial report. Treatment-related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab-plus-ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group.

Conclusions: Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505 .).

Figure 1. Kaplan–Meier Estimates of Survival

Panel A shows the Kaplan–Meier estimates of progression-free survival as assessed by the investigator. Patients were followed for a minimum of 36 months (dashed line). The median progression-free survival was 11.5 months (95% CI, 8.7 to 19.3) in the nivolumab-plus-ipilimumab group and 6.9 months (95% CI, 5.1 to 9.7) in the nivolumab group, as compared with 2.9 months (95% CI, 2.8 to 3.2) in the ipilimumab group. The rate of progression-free survival at 2 years was 43% in the nivolumab-plus-ipilimumab group and 37% in the nivolumab group, as compared with 12% in the ipilimumab group. The 3-year rate of progression-free survival was 39% in the nivolumab-plus-ipilimumab group and 32% in the nivolumab group, as compared with 10% in the ipilimumab group. Panel B shows the Kaplan–Meier estimates of overall survival. The median overall survival was not reached in the nivolumab-plus-ipilimumab group and was 37.6 months (95% CI, 29.1 to not reached) in the nivolumab group and 19.9 months (95% CI, 16.9 to 24.6) in the ipilimumab group. The overall survival rate at 2 years was 64% in the nivolumab-plus-ipilimumab group and 59% in the nivolumab group, as compared with 45% in the ipilimumab group. The 3-year rate of overall survival was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. Symbols (tick marks, triangles, and circles) indicate censored data.

Figure 2. (facing page). Subgroup Analysis of Overall Survival and Progression-free Survival at 3 Years

Shown are descriptive subgroup analyses of overall survival and progression-free survival in prespecified subgroups of patients who received combination therapy with nivolumab plus ipilimumab (Nivo+Ipi), as compared with nivolumab monotherapy (Nivo). Results are expressed as unadjusted hazard ratios in the analyses of progression-free survival (hazard ratio for progression, relapse, or death) and overall survival (hazard ratio for death) among patients who received combination therapy with nivolumab plus ipilimumab, as compared with nivolumab monotherapy; the 3-year rates of overall survival and progression-free survival are also shown. Eastern Cooperative Oncology Group (ECOG) performance-status scores are assessed on a 5-point scale, with higher scores indicating greater disability; a score of 0 indicates no symptoms, and 1 mild symptoms. LDH denotes lactate dehydrogenase, PD-L1 programmed death ligand 1, and ULN upper limit of the normal range.

Figure 3. Overall Survival among Patients with or without BRAF Mutations

Panel A shows the Kaplan–Meier estimates of overall survival among patients with BRAF mutations. Patients were followed for a minimum of 36 months (dashed line). The median overall survival was not reached in either nivolumab-containing group and was 24.6 months (95% CI, 17.9 to 31.0) in the ipilimumab group. Symbols (tick marks, triangles, and circles) indicate censored data. Panel B shows the Kaplan–Meier estimates of overall survival among patients without BRAF mutations. The median overall survival was 39.1 months (95% CI, 27.6 to not reached) in the nivolumab-plus-ipilimumab group and 35.8 months (95% CI, 25.8 to not reached) in the nivolumab group, as compared with 18.5 months (95% CI, 14.1 to 22.7) in the ipilimumab group.