Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma | Dermatology | JAMA | JAMA Network
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Original Investigation
April 19, 2016

Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma

Author Affiliations
  • 1Division of Hematology and Oncology, University of California-Los Angeles, Los Angeles
  • 2Department of Hematology/Oncology, The Angeles Clinic and Research Institute, Los Angeles, California
  • 3Department of Hematology/Oncology, University of California-San Francisco, San Francisco
  • 4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 5Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
  • 6Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital and Melanoma Institute Australia, Sydney, Australia
  • 7Department of Clinical Medicine, Macquarie University, Sydney, Australia
  • 8Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
  • 9Department of Clinical Research, South Texas Accelerated Research Therapeutics, San Antonio
  • 10Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston
  • 11Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida
  • 12Division of Hematology and Oncology, Abramson Cancer Center at the University of Pennsylvania, Philadelphia
  • 13Department of Medicine, University of Sydney, Sydney, Australia
  • 14Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota
  • 15Department of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida
  • 16Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 17Department of Hematology/Oncology, Massachusetts General Hospital, Boston
  • 18Department of Medical Oncology, Gustave-Roussy Cancer Campus and Paris Sud University, Villejuif Paris-Sud, France
  • 19Department of Clinical Oncology, Merck & Co, Inc, Kenilworth, New Jersey
  • 20BARDS, Merck & Co, Inc, Kenilworth, New Jersey
JAMA. 2016;315(15):1600-1609. doi:10.1001/jama.2016.4059

Importance  The programmed death 1 (PD-1) pathway limits immune responses to melanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab.

Objective  To characterize the association of pembrolizumab with tumor response and overall survival among patients with advanced melanoma.

Design, Settings, and Participants  Open-label, multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013). Median duration of follow-up was 21 months. The study was performed in academic medical centers in Australia, Canada, France, and the United States. Eligible patients were aged 18 years and older and had advanced or metastatic melanoma. Data were pooled from 655 enrolled patients (135 from a nonrandomized cohort [n = 87 ipilimumab naive; n = 48 ipilimumab treated] and 520 from randomized cohorts [n = 226 ipilimumab naive; n = 294 ipilimumab treated]). Cutoff dates were April 18, 2014, for safety analyses and October 18, 2014, for efficacy analyses.

Exposures  Pembrolizumab 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks continued until disease progression, intolerable toxicity, or investigator decision.

Main Outcomes and Measures  The primary end point was confirmed objective response rate (best overall response of complete response or partial response) in patients with measurable disease at baseline per independent central review. Secondary end points included toxicity, duration of response, progression-free survival, and overall survival.

Results  Among the 655 patients (median [range] age, 61 [18-94] years; 405 [62%] men), 581 had measurable disease at baseline. An objective response was reported in 194 of 581 patients (33% [95% CI, 30%-37%]) and in 60 of 133 treatment-naive patients (45% [95% CI, 36% to 54%]). Overall, 74% (152/205) of responses were ongoing at the time of data cutoff; 44% (90/205) of patients had response duration for at least 1 year and 79% (162/205) had response duration for at least 6 months. Twelve-month progression-free survival rates were 35% (95% CI, 31%-39%) in the total population and 52% (95% CI, 43%-60%) among treatment-naive patients. Median overall survival in the total population was 23 months (95% CI, 20-29) with a 12-month survival rate of 66% (95% CI, 62%-69%) and a 24-month survival rate of 49% (95% CI, 44%-53%). In treatment-naive patients, median overall survival was 31 months (95% CI, 24 to not reached) with a 12-month survival rate of 73% (95% CI, 65%-79%) and a 24-month survival rate of 60% (95% CI, 51%-68%). Ninety-two of 655 patients (14%) experienced at least 1 treatment-related grade 3 or 4 adverse event (AE) and 27 of 655 (4%) patients discontinued treatment because of a treatment-related AE. Treatment-related serious AEs were reported in 59 patients (9%). There were no drug-related deaths.

Conclusions and Relevance  Among patients with advanced melanoma, pembrolizumab administration was associated with an overall objective response rate of 33%, 12-month progression-free survival rate of 35%, and median overall survival of 23 months; grade 3 or 4 treatment-related AEs occurred in 14%.

Trial Registration Identifier: NCT01295827