Combined Nivolumab and Ipilimumab or Monotherapy in Previously Untreated Melanoma

Abstract

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.)