The FDA has granted accelerated approval to nivolumab (Opdivo Injection, Bristol-Myers Squibb Company) in combination with ipilimumab for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.

The clinical trial that supported approval randomized (2:1) 142 patients to receive nivolumab plus ipilimumab (n=95) or ipilimumab plus placebo (n=47). Randomization was stratified by BRAF V600 mutation status based on an FDA-approved test. Patients in the nivolumab plus ipilimumab arm received nivolumab 1mg/kg and ipilimumab 3mg/kg intravenously every three weeks for four doses, then nivolumab 3mg/kg every two weeks until disease progression or unacceptable toxicity. Patients in the ipilimumab arm received ipilimumab 3mg/kg and nivolumab-matched placebo intravenously every three weeks for four doses followed by placebo. At the time of disease progression, patients on the ipilimumab arm were offered nivolumab 3mg/kg every two weeks.

Of the 109 patients with BRAF V600 wild-type melanoma, the median age was 66 years and ECOG performance score was 0 (84%) or 1 (15%). Forty-six percent had M1c disease and 20% had elevated baseline LDH.

The trial demonstrated a significant improvement in ORR. The ORR was 60% in the nivolumab plus ipilimumab group (n=72) and 11% in the ipilimumab group (n=37), an improvement in ORR of 49%. Of the 43 patients with an objective response in the nivolumab plus ipilimumab group, 9 patients (21%) with response duration ranging from three to seven months have progressed after response, died, or received subsequent therapy. The remaining 34 patients (79%) had ongoing responses at the time of final analysis; in 14 patients the duration of ongoing responses is at least six months but less than nine months and in 20 patients the duration of ongoing responses is at least nine months. In addition, there was a significant improvement in PFS for the combination group compared with the ipilimumab with an estimated median PFS of 8.9 and 4.7 months in the nivolumab plus ipilimumab and ipilimumab groups, respectively.

Among the 140 patients with BRAF V600 wild-type or mutation-positive melanoma who received at least one dose of nivolumab or ipilimumab, serious adverse reactions (62% vs. 39%), adverse reactions leading to permanent discontinuation (43% vs. 11%) or dose delay (47% vs. 22%), and grade 3 or 4 adverse reactions (69% vs. 43%) all occurred more frequently in patients receiving the combination (n= 94) compared with those receiving single-agent ipilimumab (n=46). The most frequent serious adverse reactions in patients receiving the combination were colitis (17%), diarrhea (9%), pyrexia (6%), and pneumonitis (5%). Additional clinically significant immune-mediated adverse reactions included pneumonitis, hepatitis, endocrinopathies, nephritis/renal dysfunction, and rash.

Common adverse reactions (greater than or equal to 20%) in patients receiving nivolumab plus ipilimumab were rash, pruritus, headache, vomiting, and colitis. The most frequent grade 3 and 4 laboratory abnormalities occurring in at least 5% of patients receiving the combination were increased ALT, increased AST, increased lipase, increased amylase, hyponatremia, and lymphopenia.

When used in combination with ipilimumab, the recommended dose and schedule is nivolumab 1mg/kg administered as an intravenous infusion over 60 minutes, followed by ipilimumab on the same day, every three weeks for four doses. The recommended subsequent dose of nivolumab, as a single agent, is 3mg/kg as an intravenous infusion over 60 minutes every two weeks until disease progression or unacceptable toxicity.