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FDA Grants Accelerated Approval to Nivolumab in Combination With Ipilimumab in BRAF V600 Wild-Type, Unresectable, or Metastatic Melanoma

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Key Points

  • The FDA is scheduled to make a decision on this application by January 23, 2016.
  • Approval was based on demonstration of an increase in the objective response rate, prolonged response durations, and improvement in progression-free survival in the phase III CheckMate 067 study.

On September 30, 2015, the U.S. Food and Drug Administration (FDA) granted accelerated approval to nivolumab (Opdivo) in combination with ipilimumab (Yervoy) for the treatment of patients with BRAF V600 wild-type, unresectable, or metastatic melanoma. The FDA is scheduled to make a decision on this application by January 23, 2016.

Approval was based on demonstration of an increase in the objective response rate, prolonged response durations, and improvement in progression-free survival in the phase III CheckMate 067 study, an international, multicenter, double-blind, randomized, two-arm, active-controlled trial in patients who were previously untreated for unresectable or metastatic, BRAF V600 wild-type melanoma.

Trial Details

The clinical trial randomly assigned (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 at 1 mg/kg and ipilimumab at 3 mg/kg intravenously every 3 weeks for four doses, then nivolumab at 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Patients in the ipilimumab arm received ipilimumab at 3 mg/kg and nivolumab-matched placebo intravenously every 3 weeks for four doses, followed by placebo. At the time of disease progression, patients on the ipilimumab arm were offered nivolumab at 3 mg/kg every 2 weeks.

Among 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 overall response rate (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 patients (21%) with response duration ranging from 3 to 7 months have had disease progression 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 6 months but less than 9 months, and in 20 patients, the duration of ongoing responses is at least 9 months.

In addition, there was a significant improvement in progression-free survival 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 progression-free survival of 8.9 and 4.7 months in the nivolumab-plus-ipilimumab and ipilimumab groups, respectively.

Recommended Dosing

When used in combination with ipilimumab, the recommended dose and schedule is nivolumab at 1 mg/kg administered as an intravenous infusion over 60 minutes, followed by ipilimumab on the same day, every 3 weeks for four 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.

Full prescribing information is available here.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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