Nivolumab in Previously Untreated Melanoma without BRAF Mutation

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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.


  • Caroline Robert
  • Georgina V. Long
  • Benjamin Brady
  • Caroline Dutriaux
  • Michele Maio
  • Laurent Mortier
  • Jessica C. Hassel
  • Piotr Rutkowski
  • Catriona McNeil
  • Ewa Kalinka-Warzocha
  • Kerry J. Savage
  • Micaela M. Hernberg
  • Celeste Lebbe
  • Julie Charles
  • Catalin Mihalcioiu
  • Vanna Chiarion-Sileni
  • Cornelia Mauch
  • Francesco Cognetti
  • Ana Arance
  • Henrik Schmidt
  • And 8 others
  • Dirk Schadendorf
  • Helen Gogas
  • Lotta Lundgren
  • Christine Horak
  • Brian Sharkey
  • Ian M. Waxman
  • Victoria Atkinson
  • Paolo A. Ascierto
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Pages (from-to)320-330
JournalNew England Journal of Medicine
Issue number4
Publication statusPublished - 2015
Publication categoryResearch

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