Nivolumab and ipilimumab versus ipilimumab in untreated melanoma

Abstract

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. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01927419.).

Fig 1. Clinical activities

(Panel A) Tumor burden change from baseline in the sum of reference diameters of target lesion among patients receiving combination nivolumab and ipilimumab (left) or ipilimumab monotherapy (right); Horizontal reference line indicates the 30% reduction in tumor burden consistent with a RECIST 1.1 response; (Panel B) Durability of tumor regressions in patients with advanced melanoma with BRAF wild-type tumors who had objective responses to combination nivolumab and ipilimumab or ipilimumab alone according to conventional RECIST criteria. Blue bars indicate the time to and duration of response while on treatment; red bars indicate duration of response after treatment discontinuation; open circles indicate first evidence of objective response; arrows indicate ongoing response at time of analysis. (Panel C) Kaplan-Meier curves for progression-free survival of patients with BRAF wild-type tumors treated with combination nivolumab and ipilimumab or ipilimumab alone.

Fig 1. Clinical activities

(Panel A) Tumor burden change from baseline in the sum of reference diameters of target lesion among patients receiving combination nivolumab and ipilimumab (left) or ipilimumab monotherapy (right); Horizontal reference line indicates the 30% reduction in tumor burden consistent with a RECIST 1.1 response; (Panel B) Durability of tumor regressions in patients with advanced melanoma with BRAF wild-type tumors who had objective responses to combination nivolumab and ipilimumab or ipilimumab alone according to conventional RECIST criteria. Blue bars indicate the time to and duration of response while on treatment; red bars indicate duration of response after treatment discontinuation; open circles indicate first evidence of objective response; arrows indicate ongoing response at time of analysis. (Panel C) Kaplan-Meier curves for progression-free survival of patients with BRAF wild-type tumors treated with combination nivolumab and ipilimumab or ipilimumab alone.

Fig 1. Clinical activities

(Panel A) Tumor burden change from baseline in the sum of reference diameters of target lesion among patients receiving combination nivolumab and ipilimumab (left) or ipilimumab monotherapy (right); Horizontal reference line indicates the 30% reduction in tumor burden consistent with a RECIST 1.1 response; (Panel B) Durability of tumor regressions in patients with advanced melanoma with BRAF wild-type tumors who had objective responses to combination nivolumab and ipilimumab or ipilimumab alone according to conventional RECIST criteria. Blue bars indicate the time to and duration of response while on treatment; red bars indicate duration of response after treatment discontinuation; open circles indicate first evidence of objective response; arrows indicate ongoing response at time of analysis. (Panel C) Kaplan-Meier curves for progression-free survival of patients with BRAF wild-type tumors treated with combination nivolumab and ipilimumab or ipilimumab alone.