Adjuvant pembrolizumab confers durable RFS benefit in resected stage III melanoma
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Adjuvant pembrolizumab taken for up to 1 year conferred a durable, clinically meaningful RFS benefit for patients with resected high-risk stage III melanoma, according to study results presented during the ASCO20 Virtual Scientific Program.
The RFS improvement — observed at 3-year median follow-up of the randomized, phase 3 EORTC 1325/KEYNOTE-054 trial — remained consistent across subgroups, researchers noted.
“In the old era, for about 50 years, we tried to define the role of adjuvant therapy for stage III melanoma,” Alexander M.M. Eggermont, MD, PhD, FASCO, professor of oncology at Paris-Sud University and professor of oncological surgery and chair of the International Research Network on Cancer at Erasmus University of Rotterdam in the Netherlands, said during a presentation. “The last 5 years, we have been dedicated to evaluating drugs that are active in this setting.”
The EORTC 1325/KEYNOTE-054 trial included 1,019 adults with stage IIIA (15%), stage IIIB (46%) or stage IIIC (39%) resected melanoma metastatic to lymph nodes. Eggermont and colleagues randomly assigned patients to adjuvant pembrolizumab (Keytruda, Merck) dosed at 200 mg every 3 weeks for up to 1 year (n = 514) or placebo (n = 505) for a total of 18 doses or until disease recurrence or unacceptable toxicity.
RFS among the intent-to-treat population and among patients with PD-L1-positive tumors served as the study’s co-primary endpoints.
A previous update of the study at median follow-up of 1.25 years showed pembrolizumab improved RFS compared with placebo (HR = 0.57). This led to FDA and European Medicines Agency approval of the anti-PD-1 agent as adjuvant treatment for this patient population.
Updated results at median follow-up of 3.05 years showed superior RFS among the pembrolizumab group compared with the placebo group (190 vs. 283 RFS events; HR = 0.56; 95% CI, 0.47-0.68). Researchers observed higher 3-year RFS rates with pembrolizumab vs. placebo among 853 patients with PD-L1-positive tumors (65% vs. 46%; HR = 0.57; 95% CI, 0.43-0.74), 440 patients with BRAF-mutated tumors (62% vs. 37%; HR = 0.51; 95% CI, 0.36-0.73) and 448 patients with BRAF wild-type tumors (62% vs. 47%; HR = 0.66; 95% CI, 0.46-0.95).
“We have shown that longer follow-up confirms a very sustained RFS benefit for pembrolizumab compared with placebo,” Eggermont said. “We will report on distant metastasis-free survival when they are ready in the next 6 or 7 months.”
Reference:
Eggermont AMM, et al. Abstract 10000. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
Perspective
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Gino In, MD
Updates from this study are reassuring, with confirmatory data showing the continued benefit of pembrolizumab and other PD-1 inhibitors in advanced, resectable melanoma. PD-1 therapy led to an absolute benefit of nearly 15%, with an impressive HR of 0.57. Now, with a median follow-up of 36 months, we see that 3-year RFS rates for patients receiving adjuvant PD-1 therapy are 64%, compared with 44% for those who received placebo, with a benefit of about 20% (HR = 0.56). This trend of deepening benefit from checkpoint inhibitors over time is similar to what we have seen in other studies. It speaks to the mechanism of this therapy and its ability to modulate tumor immune surveillance, even beyond the 1-year treatment period.
Last year, we received updates from CheckMate 238, a very similar study. In that study, researchers randomly assigned patients with stage IIIB or stage IV melanoma to adjuvant PD-1 inhibition with nivolumab or adjuvant CTLA-4 inhibition. In that study, patients who received adjuvant PD-1 therapy had RFS rates of nearly 60%.
When you have multiple, large phase 3 studies demonstrating that patients who receive adjuvant PD-1 therapy have a much lower likelihood of recurrence or death, this is fairly compelling evidence. Adjuvant PD-1 therapy really should be considered the standard of care for patients at high risk for recurrence after resection of advanced melanoma, given the considerable benefit and reasonable toxicity profile.
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