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Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma

Michael A. Postow, M.D., Jason Chesney, M.D., Ph.D., Anna C. Pavlick, D.O., Caroline Robert, M.D. et al.

NEJM, April 20, 2015DOI: 10.1056/NEJMoa1414428

Editors’ comment: Dr. Paolo Ascierto
The CTLA-4 and PD-L1 pathways inhibit the antitumor immunity with two different and complementary mechanisms. For this reason in the last few years emerged the conviction that the combination of two different checkpoint inhibitors could lead to an higher improvement in terms of response and survival in patients with advanced melanoma. A previous phase I study showed an high response rates and a 2 years survival rate of 79% for patients treated with the combination of ipilimumab and nivolumab. In this Phase II study, 179 patients were randomized to receive the combination of ipilimumab and nivolumab vs ipilimumab alone. The study’s results confirmed the superiority of the combination in terms of effectiveness, showing an increase in ORR and PFS in all subgroups of patients, regardless of the BRAF mutational status and of the PD-L1 expression

Background

In a phase 1 dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high rate of objective response, including complete responses, among patients with advanced melanoma.

Methods

In this double-blind study involving 142 patients with metastatic melanoma who had not previously received treatment, we randomly assigned patients in a 2:1 ratio to receive ipilimumab (3 mg per kilogram of body weight) combined with either nivolumab (1 mg per kilogram) or placebo once every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) or placebo every 2 weeks until the occurrence of disease progression or unacceptable toxic effects. The primary end point was the rate of investigator-assessed, confirmed objective response among patients with BRAF V600 wild-type tumors.

Results

Among patients with BRAF wild-type tumors, the rate of confirmed objective response was 61% (44 of 72 patients) in the group that received both ipilimumab and nivolumab (combination group) versus 11% (4 of 37 patients) in the group that received ipilimumab and placebo (ipilimumab-monotherapy group) (P<0.001), with complete responses reported in 16 patients (22%) in the combination group and no patients in the ipilimumab-monotherapy group. The median duration of response was not reached in either group. The median progression-free survival was not reached with the combination therapy and was 4.4 months with ipilimumab monotherapy (hazard ratio associated with combination therapy as compared with ipilimumab monotherapy for disease progression or death, 0.40; 95% confidence interval, 0.23 to 0.68; P<0.001). Similar results for response rate and progression-free survival were observed in 33 patients with BRAF mutation–positive tumors. Drug-related adverse events of grade 3 or 4 were reported in 54% of the patients who received the combination therapy as compared with 24% of the patients who received ipilimumab monotherapy. Select adverse events with potential immunologic causes were consistent with those in a phase 1 study, and most of these events resolved with immune-modulating medication.

Conclusions

The objective-response rate and the progression-free survival among patients with advanced melanoma who had not previously received treatment were significantly greater with nivolumab combined with ipilimumab than with ipilimumab monotherapy. Combination therapy had an acceptable safety profile.