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Original Investigation
October 25, 2018

Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial

Author Affiliations
  • 1Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy
  • 2Melanoma Institute Australia, Sydney, New South Wales, Australia
  • 3Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
  • 4Department of Medical Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, New South Wales, Australia
  • 5Department of Medicine, Institute Gustave Roussy, Villejuif, France
  • 6Medical Oncology and Haematology, Cabrini Health, Melbourne, Victoria, Australia
  • 7Dermatology Service, University Hospital of Bordeaux, Bordeaux, France
  • 8UOC Oncological Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy
  • 9Clinique de Dermatologie, Unité d’Onco-Dermatologie, Institut National de la Santé et de la Recherche Médicale (INSERM) U1189, Centre Hospitalier Régional Universitaire de Lille, Lille, France
  • 10Department of Dermatology, University Hospital Heidelberg and National Center for Tumor Diseases, Heidelberg, Germany
  • 11Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute–Oncology Center, Warsaw, Poland
  • 12Chris O’Brien Lifehouse, Melanoma Institute Australia, Camperdown, New South Wales
  • 13Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
  • 14Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland
  • 15Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada
  • 16Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland
  • 17Assistance Publique–Hôpitaux de Paris Dermatology and Centre d’Investigation Clinique, University Paris Diderot INSERM U976, Saint Louis Hospital, Paris, France
  • 18Institute for Advanced Biosciences, Université Grenoble Alpes/INSERM U1209/CNRS UMR 5309 Joint Research Center, Grenoble, France
  • 19Dermatology Department, Grenoble Alpes University Hospital, Grenoble, France
  • 20Department of Oncology, McGill University, Montreal, Quebec, Canada
  • 21Melanoma Cancer Unit, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, Padua, Italy
  • 22Department of Dermatology, University Hospital Cologne, Cologne, Germany
  • 23Division of Oncology, Regina Elena Institute, Rome, Italy
  • 24Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
  • 25Hospital Clinic and Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
  • 26Center for Cancer Immune Therapy, Herlev Hospital, Herlev, Denmark
  • 27Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
  • 28Department of Dermatology, University Hospital Essen, Essen, Germany
  • 29German Cancer Consortium, Heidelberg, Germany
  • 30First Department of Medicine, Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece
  • 31Global Biometric Sciences, Bristol-Myers Squibb, Princeton, New Jersey
  • 32Oncology Clinical Development, Bristol-Myers Squibb, Princeton, New Jersey
  • 33Princess Alexandra Hospital, University of Queensland, Woolloongabba, Queensland, Australia
  • 34Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, Queensland, Australia
JAMA Oncol. 2019;5(2):187-194. doi:10.1001/jamaoncol.2018.4514
Key Points

Question  What were 3-year outcomes with nivolumab vs dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma?

Findings  In this follow-up of a randomized phase 3 trial, 3-year overall survival rates for nivolumab and dacarbazine were 51.2% and 21.6%, respectively, with median overall survival of 37.5 months and 11.2 months, respectively. Treatment-related grade 3/4 adverse events were reported in 15.0% (31 of 206) of nivolumab-treated patients and in 17.6% (36 of 205) of dacarbazine-treated patients.

Meaning  Nivolumab led to improved 3-year overall survival vs dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma, with no new safety signals observed.


Importance  This analysis provides long-term follow-up in patients with BRAF wild-type advanced melanoma receiving first-line therapy based on anti–programmed cell death 1 receptor inhibitors.

Objective  To compare the 3-year survival with nivolumab vs that with dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma.

Design, Setting, and Participants  This follow-up of a randomized phase 3 trial analyzed 3-year overall survival data from the randomized, controlled, double-blind CheckMate 066 phase 3 clinical trial. For this ongoing, multicenter academic institution trial, patients were enrolled from January 2013 through February 2014. Eligible patients were 18 years or older with confirmed unresectable previously untreated stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 but without a BRAF mutation.

Interventions  Patients were treated until progression or unacceptable toxic events with nivolumab (3 mg/kg every 2 weeks plus dacarbazine-matched placebo every 3 weeks) or dacarbazine (1000 mg/m2 every 3 weeks plus nivolumab-matched placebo every 2 weeks).

Main Outcome and Measure  Overall survival.

Results  At minimum follow-ups of 38.4 months among 210 participants in the nivolumab group (median age, 64 years [range, 18-86 years]; 57.6% male) and 38.5 months among 208 participants in the dacarbazine group (median age, 66 years [range, 25-87 years]; 60.1% male), 3-year overall survival rates were 51.2% (95% CI, 44.1%-57.9%) and 21.6% (95% CI, 16.1%-27.6%), respectively. The median overall survival was 37.5 months (95% CI, 25.5 months–not reached) in the nivolumab group and 11.2 months (95% CI, 9.6-13.0 months) in the dacarbazine group (hazard ratio, 0.46; 95% CI, 0.36-0.59; P < .001). Complete and partial responses, respectively, were reported for 19.0% (40 of 210) and 23.8% (50 of 210) of patients in the nivolumab group compared with 1.4% (3 of 208) and 13.0% (27 of 208) of patients in the dacarbazine group. Additional analyses were performed on outcomes with subsequent therapies. Treatment-related grade 3/4 adverse events occurred in 15.0% (31 of 206) of nivolumab-treated patients and in 17.6% (36 of 205) of dacarbazine-treated patients. There were no deaths due to study drug toxic effects.

Conclusions and Relevance  Nivolumab led to improved 3-year overall survival vs dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma.

Trial Registration  ClinicalTrials.gov identifier: NCT01721772