Addition of Nivolumab to Ipilimumab Improves Response Rate and Progression-Free Survival in Previously Untreated Advanced Melanoma
In a phase II study reported in The New England Journal of Medicine, Postow et al found that dual checkpoint inhibitor therapy with the anti–CTLA-4 antibody ipilimumab (Yervoy) and the anti–PD-1 monoclonal antibody nivolumab (Opdivo) produced greater response rates and prolonged progression-free survival vs ipilimumab alone in patients with previously untreated advanced melanoma.
Study Details
In this double-blind trial, 142 patients from the United States and France were randomly assigned 2:1 between September 2013 and February 2014 to receive ipilimumab at 3 mg/kg combined with either nivolumab at 1 mg/kg (n = 95, including 72 with BRAF wild-type tumors) or placebo (n = 47, including 37 with BRAF wild-type tumors) once every 3 weeks for four doses, followed by nivolumab at 3 mg/kg or placebo every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed confirmed objective response among patients with BRAF V600 wild-type tumors.
Among all patients, the combination and ipilimumab groups were generally balanced for age (median, 64 and 67 years), sex (66% and 68% male), stage (III in 11% and 19%, IV in 89% and 81%), Eastern Cooperative Oncology Group performance status (0 for 83% and 79%, 1 for 15% and 21%), metastasis stage (M0 in 8% and 11%, M1a in 16% and 17%, M1b in 28% and 26%, M1c in 46% and 45%), lactate dehydrogenase level > upper limit of normal (25% and 23%), and no history of brain metastases (95% and 100%).
Outcome in BRAF Wild-Type Patients
Among patients with BRAF wild-type tumors, objective response was observed in 61% of patients (44/72) in the nivolumab-ipilimumab group vs 11% of patients (4/37) in the ipilimumab group (P < .001); complete response occurred in 16 patients (22%) in the combination group and no patients in the ipilimumab group. Median duration of response was not reached in either group. Median progression-free survival was not reached in the combination group vs 4.4 months in the ipilimumab group (hazard ratio [HR] = 0.40, P < .001).
Outcome in BRAF-Mutant Patients
Among patients with BRAF V600–mutant tumors, the objective response rate was 52% (12/23) vs 10% (1/10), with five patients in the combination group (22%) having complete response. Median progression-free survival was 8.5 months vs 2.7 months (HR = 0.38, 95% confidence interval = 0.15–1.00).
In the combination group, objective response rates were 58% in patients with PD-L1–positive tumors and 55% in those with PD-L1–negative tumors. In the ipilimumab group, the respective response rates were 18% and 4%.
Adverse Events
Treatment-related adverse events of grade 3 or 4 were reported in 54% of the combination group and 24% of the ipilimumab group, with the most common in the combination group being colitis (17% vs 7% in the ipilimumab group), diarrhea (11% vs 11%), elevated ALT (11% vs 0%), and increased lipase (9% vs 2%). Treatment-related adverse events led to discontinuation of study treatment in 38% vs 13%.
The investigators concluded: “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.”
F. Stephen Hodi, MD, of Dana-Farber Cancer Institute, is the corresponding author for the New England Journal of Medicine article. Jedd D. Wolchok, MD, PhD, of Memorial Sloan Kettering Cancer Center, contributed equally to the article.
The study was funded by Bristol-Myers Squibb. For full disclosures of the study authors, visit www.nejm.org.
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