Adjuvant pembrolizumab therapy after surgery for renal-cell carcinoma was approved on the basis of a significant improvement in disease-free survival in the KEYNOTE-564 trial. Whether the results regarding overall survival from the third prespecified interim analysis of the trial would also favor pembrolizumab was uncertain.
Methods
In this phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 1:1 ratio) participants with clear-cell renal-cell carcinoma who had an increased risk of recurrence after surgery to receive pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent. A significant improvement in disease-free survival according to investigator assessment (the primary end point) was shown previously. Overall survival was the key secondary end point. Safety was a secondary end point.
Results
A total of 496 participants were assigned to receive pembrolizumab and 498 to receive placebo. As of September 15, 2023, the median follow-up was 57.2 months. The disease-free survival benefit was consistent with that in previous analyses (hazard ratio for recurrence or death, 0.72; 95% confidence interval [CI], 0.59 to 0.87). A significant improvement in overall survival was observed with pembrolizumab as compared with placebo (hazard ratio for death, 0.62; 95% CI, 0.44 to 0.87; P=0.005). The estimated overall survival at 48 months was 91.2% in the pembrolizumab group, as compared with 86.0% in the placebo group; the benefit was consistent across key subgroups. Pembrolizumab was associated with a higher incidence of serious adverse events of any cause (20.7%, vs. 11.5% with placebo) and of grade 3 or 4 adverse events related to pembrolizumab or placebo (18.6% vs. 1.2%). No deaths were attributed to pembrolizumab therapy.
Conclusions
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. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.)
KEYNOTE-564 is a phase III clinical trial evaluating the efficacy and safety of pembrolizumab, an anti-PD-1 therapy, as adjuvant treatment for patients with renal cell carcinoma (RCC) following nephrectomy. The trial focuses on disease-free survival (DFS) as a primary endpoint, with overall survival (OS) and safety as secondary endpoints.
At median follow up of 57.2 months, a total of 55 participants in the pembrolizumab group and 86 participants in the placebo group had died. The trial demonstrated estimated overall survival (OS) difference at 48 months 91.2% in the pembrolizumab group, as compared with 86.0% in the placebo group. A significant improvement in overall survival was observed with pembrolizumab as compared with placebo (hazard ratio for death, 0.62; 95% CI, 0.44 to 0.87; P=0.005).
Pembrolizumab was associated with a higher incidence of serious adverse events of any cause (20.7%, vs. 11.5% with placebo) and of grade 3 or 4 adverse events related to pembrolizumab or placebo (18.6% vs. 1.2%). No deaths were attributed to pembrolizumab therapy.
This is the very first adjuvant treatment trial with OS benefit in RCC, with all the other trials being negative. There are many dissimilarities between the various adjuvant trials, and this should be stated while counselling the patients.
By quantifying the benefit, 19 patients need to be treated with pembrolizumab to prevent 1 death. Regarding treatment toxicity, 10 patients experience serious side effects to save a patient from death.
While KEYNOTE-564 provides robust evidence for the efficacy of pembrolizumab in improving OS for RCC patient’s post-nephrectomy, the clinical decision must balance this benefit against the potential for serious AEs. With an NNT of 19, the treatment shows substantial efficacy. However, the NNH of 10 suggests a significant risk of harm, necessitating a thorough risk-benefit discussion with patients considering individual patient factors, such as comorbidities and personal tolerance for potential toxicities that should guide clinical decisions.