As reported in the Journal of Clinical Oncology by Alexander M.M. Eggermont, MD, PhD, and colleagues, adjuvant pembrolizumab maintained a significant recurrence-free survival benefit vs placebo in patients with high-risk stage III melanoma after a median 3-year follow-up in the phase III EORTC 1325/KEYNOTE-054 trial.
The previously reported primary analysis of the trial supported the February 2019 U.S. Food and Drug Administration approval of pembrolizumab for adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection. In that analysis, at a median 1.25-year follow-up, pembrolizumab significantly prolonged recurrence-free survival vs placebo, with a hazard ratio (HR) of 0.57 (P < .0001).
Alexander M.M. Eggermont, MD, PhD
Study Details
In the double-blind trial, 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging (seventh edition; AJCC-7) stage IIIA (at least one lymph node metastasis > 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at 200 mg in a flat dose (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The co-primary endpoints were recurrence-free survival in the overall population and in patients with PD-L1–positive tumors (staining on > 1% of tumor cells or tumor-associated immune cells.) The current analysis presented outcomes at a median follow-up of 3.05 years.
Key Findings
Recurrence-free survival at 3 years was 63.7% in the pembrolizumab group vs 44.1% in the placebo group (HR = 0.56, 95% confidence interval [CI] = 0.47–0.68, P < .001). Rates at 3 years were 65.3% vs 46.4% (HR = 0.57, 99% CI = 0.43–0.74, P < .001) among 428 vs 425 patients with known PD-L1–positive status, and 56.9% vs 33.3% (HR = 0.45, 99% CI = 0.23–0.90, P = .002) among 59 vs 57 patients with known PD-L1–negative status.
The benefit of pembrolizumab was similar (P = .99) across the three AJCC-7 subgroups. Recurrence-free survival at 3 years was 81.2% vs 66.3% in patients with stage IIIA, 65.7% vs 47.0% in those with stage IIIB, and 54.3% vs 32.3% in those with stage IIIC disease, with respective hazard ratios of 0.50 (99% CI = 0.22–1.16), 0.56 (99% CI = 0.39–0.81), and 0.57 (99% CI = 0.40–0.81).
“In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in recurrence-free survival at 3-year median follow-up. This improvement was consistent across subgroups.”— Alexander M.M. Eggermont, MD, PhD, and colleagues
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The benefit was also similar (P = .90) across the four AJCC-8 subgroups. Rates at 3 years were 82.6% vs 67.4% in patients with stage IIIA, 70.4% vs 51.7% in those with stage IIIB, 59.6% vs 35.2% in those with stage IIIC, and 45.0% vs 22.2% in those with stage IIID disease, with respective hazard ratios of 0.43 (99% CI = 0.13–1.43), 0.57 (99% CI = 0.36–0.90), 0.51 (99% CI = 0.37–0.70), and 0.68 (99% CI = 0.24–1.91).
The benefit of pembrolizumab was consistent according to BRAF mutation status. Rates at 3 years were 62.0% vs 37.1% (HR = 0.51, 99% CI = 0.36–0.73) among 209 vs 231 patients with BRAF V600E/K–mutated disease and 61.8% vs 46.5% (HR = 0.66, 99% CI = 0.46–0.95) among 234 vs 214 patients with BRAF wild-type disease.
The investigators concluded, “In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in recurrence-free survival at 3-year median follow-up. This improvement was consistent across subgroups.”
Dr. Eggermont, of Princess Máxima Center, Utrecht, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Merck & Co. For full disclosures of the study authors, visit ascopubs.org.
