Nivolumab in Previously Untreated Melanoma Without BRAF Mutation

N Engl J Med. 2015 Jan 22;372(4):320-30. doi: 10.1056/NEJMoa1412082. Epub 2014 Nov 16.

Abstract

Background: Nivolumab was associated with higher rates of objective response than chemotherapy in a phase 3 study involving patients with ipilimumab-refractory metastatic melanoma. The use of nivolumab in previously untreated patients with advanced melanoma has not been tested in a phase 3 controlled study.

Methods: We randomly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks and dacarbazine-matched placebo every 3 weeks) or dacarbazine (at a dose of 1000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks). The primary end point was overall survival.

Results: At 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P<0.001). The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P<0.001). The objective response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P<0.001). The survival benefit with nivolumab versus dacarbazine was observed across prespecified subgroups, including subgroups defined by status regarding the programmed death ligand 1 (PD-L1). Common adverse events associated with nivolumab included fatigue, pruritus, and nausea. Drug-related adverse events of grade 3 or 4 occurred in 11.7% of the patients treated with nivolumab and 17.6% of those treated with dacarbazine.

Conclusions: Nivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation. (Funded by Bristol-Myers Squibb; CheckMate 066 ClinicalTrials.gov number, NCT01721772.).

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal / adverse effects
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Dacarbazine / administration & dosage*
  • Dacarbazine / adverse effects
  • Disease-Free Survival
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / mortality
  • Melanoma / secondary
  • Middle Aged
  • Nivolumab
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / genetics
  • Survival Rate
  • Young Adult

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Nivolumab
  • Dacarbazine
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf

Associated data

  • ClinicalTrials.gov/NCT01721772