As reported in The New England Journal of Medicine by Toni K. Choueiri, MD, FASCO, and colleagues, the third prespecified interim analysis of overall survival in the phase III KEYNOTE-564 trial has shown a significant benefit with adjuvant pembrolizumab vs placebo in patients with clear cell renal cell carcinoma who are at an increased risk of recurrence after surgery.

The trial supported the November 2021 approval of adjuvant pembrolizumab in this setting on the basis of superior disease-free survival, the study’s primary endpoint.  

Toni K. Choueiri, MD, FASCO

Study Details

In the multinational, double-blind trial, 994 patients were randomly assigned 1:1 to receive adjuvant pembrolizumab at 200 mg (n = 496) or placebo (n = 498) every 3 weeks for up to 17 cycles or until disease recurrence or unacceptable toxicity. Overall survival was the key secondary endpoint.

Overall Survival

At data cutoff in September 2023, median follow-up was 57.2 months (range = 47.9–74.5 months). Estimated overall survival at 48 months was 91.2% (95% confidence interval [CI] = 88.3%–93.4%) in the pembrolizumab group vs 86.0% (95% CI = 82.6%–88.8%) in the placebo group (hazard ratio [HR] = 0.62, 95% CI = 0.44–0.87, P = .005). Rates at 24 and 36 months were 96.3% vs 93.9% and 93.9% vs 89.5%, respectively.

The disease-free survival benefit with pembrolizumab was consistent with that seen in previous analyses (HR = 0.72, 95% CI = 0.59–0.87). Disease-free survival rates at 24, 36, and 48 months were 78.2% vs 67.2%, 72.4% vs 62.9%, and 64.9% vs 56.6%, respectively.

Among patients with disease recurrence, 128 of 161 (79.5%) in the pembrolizumab group vs 171 of 210 (81.4%) in the placebo group received some type of subsequent therapy. Among these patients, 79.5% vs 84.3% received systemic drug therapy, 24.2% vs 19.8% received radiation therapy, and 27.3% vs 29.1% received further surgery. Among patients receiving further systemic therapy, 41.0% vs 69.7% received anti–PD-1 or anti–PD-L1 agents.

Adverse Events

The safety analysis was consistent with prior reports. Overall, for the pembrolizumab group vs the placebo group, adverse events led to discontinuation of study treatment in 21.1% vs 2.2%, serious adverse events occurred in 20.7% vs 11.5%, and treatment-related grade 3 or 4 adverse events occurred in 18.6% vs 1.2%. A total of 10 treatment-related serious adverse events occurred in the pembrolizumab group at > 90 days after discontinuation of study treatment. The incidence of immune-mediated adverse events and infusion reactions was 36.5% vs 7.3%. No treatment-related deaths were reported.

The investigators concluded: “Adjuvant pembrolizumab was associated with a significant and clinically meaningful improvement in overall survival, as compared with placebo, among participants with clear cell renal cell carcinoma at increased risk for recurrence after surgery.”

Dr. Choueiri, of Dana-Farber Cancer Institute and Harvard Medical School, is the corresponding author of The New England Journal of Medicine article.

Disclosure: The study was funded by Merck Sharp and Dohme, a subsidiary of Merck. For full disclosures of the study authors, visit nejm.org.