Adjuvant Pembrolizumab Improves RFS in Melanoma

Adjuvant pembrolizumab reduced the risk of recurrence by 43% in patients with stage III resected high-risk melanoma.

Roger Dansey, MD

Adjuvant pembrolizumab (Keytruda) reduced the risk of recurrence by 43% in patients with stage III resected high-risk melanoma, according to findings from the phase III EORTC1325/KEYNOTE-054 trial.1

The hazard ratio for recurrence-free survival (RFS) was 0.57 for pembrolizumab versus placebo (98.4% CI, 0.43-0.74; P <.0001). There were no new safety concerns in the KEYNOTE-054 trial compared with outcomes reported in previous studies of the PD-1 inhibitor.

The study remains ongoing so that investigators can evaluate additional key outcomes measures, such as overall survival (OS). Merck (MSD), the manufacturer of pembrolizumab, reported in a press release that the full results from the trial will be shared at a future medical meeting and submitted to regulatory authorities.

“This result shows a significant advancement for patients that could potentially change the way melanoma is treated in the future,” Alexander Eggermont, MD, PhD, study chair, director General at the Gustave Roussy Cancer Institute, Professor of Oncology, University of Paris-Saclay, said in a statement.

The double-blind, phase III KEYNOTE-054 study (NCT02362594) included 1019 patients with resected high-risk melanoma (stage IIIA [>1 mm metastasis], IIIB, and IIIC). Patients were randomized to pembrolizumab at a flat dose of 200 mg IV on day 1 of each 21-day cycle for up to 1 year or placebo IV on day 1 of each 21-day cycle for up to 1 year. Altogether, this comprises 18 outpatient administrations. The primary endpoint is RFS overall and specifically in PD-L1—positive patients. Secondary outcomes measures include OS and distant metastases–free survival, also in both the entire population and in those with PD-L1 expression.

“This has been a great collaboration between Merck and the EORTC and the findings from this interim analysis show the potential for Keytruda to significantly prolong the time before the disease recurs in patients with high-risk melanoma,” Roger Dansey, MD, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories, said in a statement. “This result demonstrates the meaningful benefit that Keytruda offers for patients with melanoma. We thank the patients, investigators and our partners at the EORTC for their important contributions to this study.”

In December 2017, the FDA has approved the PD-1 inhibitor nivolumab (Opdivo) as an adjuvant treatment for patients with completely resected melanoma with lymph node involvement or metastatic disease, based on findings from the phase III CheckMate-238 trial.2

In the randomized trial, the RFS rate at 18 months with nivolumab was 66.4% (95% CI, 61.8%-70.6%) compared with 52.7% (95% CI, 47.8%-57.4%) for the CTLA-4 inhibitor ipilimumab (Yervoy) in patients with stage IIIB/C or IV melanoma. There was a 35% reduction in the risk of recurrence with nivolumab versus ipilimumab (HR, 0.65; 95% CI, 0.53-0.80; P <.0001).

Ipilimumab was approved in October 2015 for the adjuvant treatment of patients with stage III melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection, including total lymphadenectomy. The approval was based on results from the phase III EORTC 18071 trial, in which adjuvant ipilimumab at a 10 mg/kg dose reduced the risk of recurrence by 25% versus placebo (HR, 0.75; 95% CI, 0.64-0.90; P <.002).3


  1. Merck’s KEYTRUDA® (pembrolizumab) Significantly Improved Recurrence-Free Survival Compared to Placebo as Adjuvant Therapy in Patients with Stage 3 Resected High-Risk Melanoma (EORTC1325/KEYNOTE-054). Merck. Published online and accessed January 8, 2018.
  2. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med. 2017; 377:1824-1835.
  3. Eggermont AM, Chiarion-Sileni V, Grob JJ et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16(5):522-530.
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