BOSTON — A third prespecified interim analysis of the KEYNOTE-564 trial has determined that adjuvant pembrolizumab after surgery 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.
Pembrolizumab, marketed as Keytruda, was approved on the basis of a significant improvement in disease-free survival in the KEYNOTE-564 trial. Dana–Farber Cancer Institute, Harvard Medical School and Beth Israel Deaconess Medical Center, all in Boston and colleagues, recently explored whether the results regarding overall survival from the third prespecified interim analysis of the trial would also favor pembrolizumab.
For the phase 3, double-blind, placebo-controlled trial, with results published recently in the New England Journal of Medicine, the study team randomly assigned 496 participants with clear-cell renal-cell carcinoma who had an increased risk of recurrence after surgery to receive 200 mg of pembrolizumab or placebo (498 participants) every 3 weeks for up to 17 cycles (about a year’s worth or until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent.1
“A significant improvement in disease-free survival according to investigator assessment (the primary end point) was shown previously,” the authors wrote. “Overall survival was the key secondary end point. Safety was a secondary end point.”
As of Sept. 15, 2023, a median follow-up of 57.2 months, results indicated that 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),” according to the researchers. “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.”
The study also noted that 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, however.
The authors concluded that 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.”
They added, “Although improved disease-free survival has been reported before with adjuvant anti–PD-1 or anti–PD-L1 therapy (e.g., among patients with melanoma), our trial also provides evidence of an overall survival benefit with such therapy. Cross-tumor comparisons are very complex owing to the distinct immune responsiveness and tumor microenvironment of different cancers.”
- Choueiri TK, Tomczak P, Park SH, Venugopal B, et. Al.; KEYNOTE-564 Investigators. Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma. N Engl J Med. 2024 Apr 18;390(15):1359-1371. doi: 10.1056/NEJMoa2312695. PMID: 38631003.