Background The results of phase 1 and phase 2 studies suggest that nivolumab (a PD-1 checkpoint inhibitor) and ipilimumab (a CTLA-4 checkpoint inhibitor) have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab combined with ipilimumab versus ipilimumab alone were evaluated in patients with metastatic melanoma. Methods We randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma, in 1:1:1 ratio, to nivolumab alone (3 mg per kilogram of body weight every 2 weeks), or to nivolumab (at a dose of 1 mg per kilogram) plus ipilimumab (at a dose of 3 mg per kilogram) every 3 weeks for 4 doses followed by nivolumab (3 mg per kilogram every 2 weeks), or to ipilimumab alone (3 mg per kilogram every 3 weeks for 4 doses). Progression-free and overall survival were co-primary end points. Patients continue to be followed for overall survival. Results Median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) for nivolumab plus ipilimumab as compared with 2.9 months (95% CI, 2.8 to 3.4) for ipilimumab alone (hazard ratio, 0.42; 95% CI, 0.31 to 0.57; P<0.00001), and was 6.9 months (95% CI, 4.3 to 9.5) for nivolumab alone (hazard ratio in the comparison with ipilimumab alone, 0.57; 95% CI, 0.43 to 0.76; P<0.00001). In PD-L1-positive patients, median progression-free survival was 14.0 months in both the nivolumab plus ipilimumab and nivolumab alone groups, but in PD-L1-negative patients, progression-free survival was longer with the combination as compared with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] versus 5.3 months [95% CI, 2.8 to 7.1]). Grade 3–4 drug-related adverse events occurred in 16.3%, 55.0%, and 27.3% of patients in the nivolumab, nivolumab plus ipilimumab, and ipilimumab alone groups, with 1, 0, and 1 drug-related deaths, respectively. Conclusions Nivolumab alone or combined with ipilimumab significantly improved progression-free survival, as compared with ipilimumab, among previously untreated patients with metastatic melanoma. Results with the combination versus either agent alone suggest complementary activity between PD-1 and CTLA-4 blockade, particularly for patients with PD-L1-negative tumors. (Funded by Bristol-Myers Squibb; CheckMate 067, ClinicalTrials.gov number, NCT01844505.)

Background Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation. Methods We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths. Results At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. Conclusions Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann–La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.)

Nivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation. (Funded by Bristol-Myers Squibb; CheckMate 066 ClinicalTrials.gov number, NCT01721772.).

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.)

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