On September 30, 2015, the US Food and Drug Administration (FDA) 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.
Approval was based on demonstration of an increase in the objective response rate (ORR), prolonged response durations, and improvement in progression-free survival (PFS) in an international, multicenter, double-blind, randomized, 2-arm, active-controlled trial in patients who were previously untreated for unresectable or metastatic, BRAF V600 wild-type melanoma.
The clinical trial 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 1 mg/kg and ipilimumab 3 mg/kg intravenously every 3 weeks for 4 doses, then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Patients in the ipilimumab arm received ipilimumab 3 mg/kg and nivolumab-matched placebo intravenously every 3 weeks for 4 doses followed by placebo. At the time of disease progression, patients on the ipilimumab arm were offered nivolumab 3 mg/kg every 2 weeks.
Of the 109 patients with BRAF V600 wild-type melanoma, the median age was 66 years and Eastern Cooperative Oncology Group performance score was 0 (84%) or 1 (15%). Forty-six percent had M1c disease and 20% had elevated baseline lactate dehydrogenase.
The trial demonstrated a significant improvement in ORR. The ORR was 60% (95% confidence interval [CI]: 48, 71) in the nivolumab plus ipilimumab group (n = 72) and 11% (95% CI: 3, 25) in the ipilimumab group (n = 37), an improvement in ORR of 49% (95% CI: 31, 61; P <.001). Of the 43 patients with an objective response in the nivolumab plus ipilimumab group, 9 (21%) patients with response duration ranging from 3 to 7 months have progressed after response, died, or received subsequent therapy. The remaining 34 (79%) patients had ongoing responses at the time of final analysis; in 14 patients the duration of ongoing responses is >6 months but <9 months, and in 20 patients the duration of ongoing responses is >9 months. In addition, there was a significant improvement in PFS for the combination group compared with the ipilimumab group (hazard ratio 0.40 [95% CI: 0.22, 0.71]; P < .002) 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 (≥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 >5% of patients receiving the combination were increased alanine aminotransferase, increased aspartate aminotransferase, increased lipase, increased amylase, hyponatremia, and lymphopenia.
When used in combination with ipilimumab, the recommended dose and schedule is nivolumab 1 mg/kg administered as an intravenous infusion over 60 minutes, followed by ipilimumab on the same day, every 3 weeks for 4 doses. The recommended subsequent dose of nivolumab, as a single agent, is 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
US Food and Drug Administration. Nivolumab in combination with ipilimumab. Updated October 1, 2015.