Nivolumab Plus Ipilimumab Receives Expanded FDA Approval in Unresectable or Metastatic Melanoma Across BRAF Status

Key Points

  • Median progression-free survival was 11.5 months for the nivolumab-plus-ipilimumab regimen and 6.9 months for nivolumab monotherapy, vs 2.9 months for ipilimumab monotherapy.
  • Nivolumab plus ipilimumab demonstrated a 58% reduction in the risk of disease progression vs ipilimumab, while nivolumab monotherapy demonstrated a 43% risk reduction vs ipilimumab monotherapy.
  • In addition, nivolumab plus ipilimumab and nivolumab monotherapy demonstrated higher confirmed objective response rates (50% and 40%, respectively) vs ipilimumab monotherapy (14%).

Bristol-Myers Squibb announced on January 23 that the U.S. Food and Drug Administration (FDA) has approved nivolumab (Opdivo) in combination with ipilimumab (Yervoy) for the treatment of patients with BRAF V600 wild-type and BRAF V600 mutation–positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival.

This approval expands the original indication for the nivolumab and ipilimumab regimen for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma to include patients, regardless of BRAF mutational status, based on data from the phase III CheckMate 067 trial.

The FDA also expanded the use of nivolumab as a single-agent to include previously untreated BRAF mutation–positive advanced melanoma patients. The use of nivolumab as a single-agent in patients with BRAF V600 mutation–positive unresectable or metastatic melanoma is approved under accelerated approval based on progression-free survival.

Nivolumab was approved by the FDA in November 2015 for use in previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma.

CheckMate 067 Trial

CheckMate 067 is a phase III, double-blind, randomized study that evaluated nivolumab plus ipilimumab or nivolumab monotherapy vs ipilimumab monotherapy in patients with previously untreated advanced melanoma and BRAF V600–positive or wild-type mutation status. Patients were randomly assigned to receive nivolumab-plus-ipilimumab regimen, nivolumab monotherapy, or ipilimumab monotherapy and treated until progression or unacceptable toxic effects. The co-primary study endpoints were progression-free survival and overall survival.

Results from the trial demonstrated a statistically significant improvement in progression-free survival in patients with advanced melanoma treated with nivolumab plus ipilimumab (P < .0001) and with nivolumab as a single-agent (P < .0001) vs ipilimumab monotherapy. Median progression-free survival was 11.5 months (95% confidence interval [CI] = 8.9–16.7) for the nivolumab-plus-ipilimumab arm and 6.9 months (95% CI = 4.3–9.5) for nivolumab monotherapy, vs 2.9 months (95% CI = 2.8–3.4) for ipilimumab monotherapy. The nivolumab-plus-ipilimumab regimen demonstrated a 58% reduction in the risk of disease progression vs ipilimumab (hazard ratio [HR] = 0.42, 95% CI = 0.34–0.51, P < .0001), while nivolumab monotherapy demonstrated a 43% risk reduction vs ipilimumab monotherapy (HR = 0.57, 95% CI = 0.47–0.69, P < .0001).

In addition, the nivolumab-plus-ipilimumab regimen and nivolumab monotherapy demonstrated higher confirmed objective response rates (ORR; 50% and 40%; P < .0001, respectively) vs ipilimumab monotherapy (14%). The percentage of patients with a complete response was 8.9%, 8.5%, and 1.9%, favoring the regimen and nivolumab monotherapy over ipilimumab monotherapy. Partial responses were seen in 41% of patients treated with the nivolumab-plus-ipilimumab regimen, 31% of patients treated with nivolumab monotherapy, and 12% of patients treated with ipilimumab monotherapy. The nivolumab-plus-ipilimumab regimen delivered durable responses, with three of four (76%) patients experiencing an ongoing response of at least 6 months. Of patients in the nivolumab monotherapy and ipilimumab monotherapy arms, 74% and 63% experienced an ongoing response of at least 6 months, respectively.

Adverse Events

Serious adverse reactions (73% and 37%), adverse reactions leading to discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the nivolumab-plus-ipilimumab arm relative to the nivolumab arm. No overall differences in safety or efficacy were reported between elderly and younger patients.

The most common adverse reactions leading to discontinuation of the nivolumab-plus-ipilimumab regimen relative to nivolumab as a single-agent were diarrhea (8% and 1.9%), colitis (8% and 0.6%), increased ALT (4.8% and 1.3%), increased AST (4.5% and 0.6%), and pneumonitis (1.9% and 0.3%). The most frequent (≥ 10%) serious adverse reactions in the nivolumab-plus-ipilimumab arm and the nivolumab arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). The most common adverse reactions (≥ 20%) reported in patients receiving the nivolumab-plus-ipilimumab regimen relative to nivolumab as a single-agent were fatigue (59% and 53%), rash (53% and 40%), diarrhea (52% and 31%), and nausea (40% and 28%). Pyrexia (37%), vomiting (28%), and dyspnea (20%) were also reported in ≥ 20% of patients receiving the nivolumab-plus-ipilimumab regimen.

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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