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Original Investigation
June 29, 2017

Nivolumab for Patients With Advanced Melanoma Treated Beyond ProgressionAnalysis of 2 Phase 3 Clinical Trials

Author Affiliations
  • 1Melanoma Institute Australia, University of Sydney, Sydney, New South Wales, Australia
  • 3Mater Hospital, North Sydney, New South Wales, Australia
  • 4Department of Medical Oncology, Moffitt Cancer Center, Tampa, Florida
  • 5now with Department of Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York
  • 6Department of Oncology, Royal Marsden Hospital, London, United Kingdom
  • 7Gallipoli Medical Research Foundation and Princess Alexandra Hospital, and University of Queensland, Queensland, Australia
  • 8Department of Dermatology and Skin Cancer, Hospital Timone APHM, Aix-Marseille University, Marseille, France
  • 9Department of Skin, University Hospital Essen, Essen, Germany
  • 10Department of Urology, University Hospital Essen, Essen, Germany
  • 11Department of Dermatology, UniversitaetsSpital, Zurich, Switzerland
  • 12Department of Medicine Institute Gustave Roussy, Gustave Roussy and Paris-Sud University, Villejuif Paris-Sud, France
  • 13Servicio de Oncología Médica, Hospital General Universitario Gregorio Marañón, Madrid, Spain
  • 14Chris O’Brien Lifehouse, Melanoma Institute Australia, Camperdown, New South Wales, Australia
  • 15Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
  • 16Department of Oncology, Aarhus University Hospital, Aarhus, Denmark
  • 17Department of Medical Oncology, Coffs Harbour Health Campus, New South Wales, Australia
  • 18Melanoma Clinic at King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Bruxelles, Belgium
  • 19Melanoma Center and Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 20Ludwig Center for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center, New York, New York
JAMA Oncol. Published online June 29, 2017. doi:10.1001/jamaoncol.2017.1588
Key Points

Question  Can patients with treatment-naive advanced melanoma derive apparent clinical benefit from nivolumab treatment beyond Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined progression without compromising safety?

Findings  In this pooled, retrospective analysis of 85 treatment-naive patients with advanced melanoma who continued nivolumab treatment beyond RECIST v1.1-defined progression in phase 3 clinical trials (CheckMate 066, CheckMate 067), 28% had a target lesion reduction of greater than 30% after progression compared with baseline, with no new or unexpected adverse events.

Meaning  Continued treatment with nivolumab may be an option to achieve further benefit without compromising safety in some patients with advanced melanoma.


Importance  Immune checkpoint inhibitors have demonstrated atypical response patterns, which may not be fully captured by conventional response criteria. There is a need to better understand the potential benefit of continued immune checkpoint inhibition beyond progression.

Objective  To evaluate the safety and potential benefit of nivolumab (anti–programmed cell death receptor 1) monotherapy beyond Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined progression.

Design, Setting, and Participants  Pooled, retrospective analysis of data from phase 3 trials of nivolumab in treatment-naive patients with advanced melanoma (CheckMate 066 or CheckMate 067) conducted at academic and clinical cancer centers. Participants were patients treated beyond first disease progression, defined as those who received their last dose of nivolumab more than 6 weeks after progression (TBP group); and patients not treated beyond progression, who discontinued nivolumab therapy before or at progression (non-TBP group). Data analyses were conducted from November 6, 2015, to January 11, 2017.

Interventions  Nivolumab (3 mg/kg every 2 weeks) administered until progression or unacceptable toxic effects. Patients could be treated beyond progression if deriving apparent clinical benefit and tolerating study drug, at the investigator’s discretion.

Main Outcomes and Measures  Tumor response and safety in TBP and non-TBP patients.

Results  Among 526 randomized patients (39% [n = 203] female; median age, 62 years [range, 18-90 years]), 306 (58%) experienced disease progression, including 85 (28%) TBP patients and 221 (72%) non-TBP patients. Twenty-four (28%) of the TBP patients had a target lesion reduction of greater than 30% after progression compared with baseline (TBP>30% group). At the time of this analysis, 65 (76%) TBP patients and 21 (87%) TBP>30% patients were still alive; 27 (32%) and 11 (46%), respectively, continued to receive treatment. Median (range) time from progression to last dose of treatment was 4.7 (1.4-25.8) months for TBP patients and 7.6 (2.4-19.4) months for TBP>30% patients. Median (range) time from progression to greater than 30% tumor reduction was 1.4 (0.2-7.0) months. Treatment-related select grade 3 to 4 adverse events were similar in the TBP and non-TBP groups (5 [6%] and 9 [4%], respectively).

Conclusions and Relevance  A substantial proportion of selected patients treated with frontline nivolumab who were clinically stable and judged to be eligible for treatment beyond RECIST v1.1–defined progression by the treating investigators derived apparent clinical benefit without compromising safety. Further analysis will help define the potential benefit of continued nivolumab treatment beyond progression.

Trial Registration  clinicaltrials.gov Identifiers: NCT01721772 (CheckMate 066) and NCT01844505 (CheckMate 067)