Adjuvant Pembrolizumab Versus Placebo in Resected Stage III Melanoma

N Engl J Med. 2018 May 10;378(19):1789-1801. doi: 10.1056/NEJMoa1802357. Epub 2018 Apr 15.

Abstract

Background: The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma.

Methods: Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated.

Results: At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group.

Conclusions: As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594 ; EudraCT number, 2014-004944-37 .).

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adjuvants, Immunologic / adverse effects
  • Adjuvants, Immunologic / therapeutic use*
  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • B7-H1 Antigen / analysis
  • B7-H1 Antigen / antagonists & inhibitors*
  • Disease-Free Survival
  • Double-Blind Method
  • Female
  • Humans
  • Infusions, Intravenous
  • Intention to Treat Analysis
  • Kaplan-Meier Estimate
  • Male
  • Melanoma / drug therapy*
  • Melanoma / mortality
  • Melanoma / surgery
  • Middle Aged
  • Neoplasm Recurrence, Local
  • Neoplasm Staging
  • Quality of Life
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / mortality
  • Skin Neoplasms / surgery
  • Survival Rate

Substances

  • Adjuvants, Immunologic
  • Antibodies, Monoclonal, Humanized
  • B7-H1 Antigen
  • CD274 protein, human
  • pembrolizumab

Associated data

  • ClinicalTrials.gov/NCT02362594
  • EudraCT/2014-004944-37