As reported in The New England Journal of Medicine by Toni K. Choueiri, MD, FASCO, of Dana-Farber Cancer Institute and Harvard Medical School, and colleagues, the third prespecified interim analysis of overall survival in the phase III KEYNOTE-564 trial has shown significant benefit with adjuvant pembrolizumab vs placebo in patients with clear cell renal cell carcinoma with an increased risk of recurrence after surgery.1
The trial supported the November 2021 approval of adjuvant pembrolizumab in this setting on the basis of superior disease-free survival, the primary endpoint.
Toni K. Choueiri, MD, FASCO
Study Details
In the multinational, double-blind trial, 994 patients were randomly assigned to receive adjuvant pembrolizumab at 200 mg (n = 496) or placebo (n = 498) every 3 weeks for up to 17 cycles or until recurrence or unacceptable toxicity. Randomization was stratified by metastatic stage of M0 vs M1 before surgery and geographic region of the setting on the basis of superior disease-free survival, the primary endpoint.
Study Details
In the multinational, double-blind trial, 994 patients were randomly assigned to receive adjuvant pembrolizumab at 200 mg (n = 496) or placebo (n = 498) every 3 weeks for up to 17 cycles or until recurrence or unacceptable toxicity. Randomization was stratified by metastatic stage of M0 vs M1 before surgery and geographic region of the United States vs other. Overall survival was the key secondary endpoint.
Overall Survival
At data cutoff (September 2023), median follow-up was 57.2 months (range = 47.9–74.5 months). Estimated overall survival rate 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). Estimated overall survival rates at 24 and 36 months were 96.3% vs 93.9% and 93.9% vs 89.5%.
In stratification subgroups, hazard ratios for overall survival in the pembrolizumab group vs the placebo group were 0.63 (95% CI = 0.44–0.90) among 467 vs 470 patients with M0 disease and 0.51 (95% CI = 0.15–1.75) among 29 vs 28 with M1 disease. The hazard ratios were 0.68 (95% CI = 0.32–1.47) among 114 vs 117 patients from the United States and 0.61 (95% CI = 0.42–0.88) among 382 vs 381 from other geographic regions.
In other subgroups, hazard ratios for overall survival for the pembrolizumab group vs the placebo group follow:
- 0.65 (95% CI = 0.31–1.38) among 124 vs 113 patients with a PD-L1 combined positive score of < 1 and 0.62 (95% CI = 0.42–0.91) among 365 vs 383 with a PD-L1 combined positive score ≥ 1;
- 0.51 (95% CI = 0.31–0.83) among 338 vs 326 patients aged < 65 and 0.77 (95% CI = 0.48–1.23) among 158 vs 172 aged ≥ 65;
- 1.08 (95% CI = 0.57–2.04) among 149 vs 139 women and 0.50 (95% CI = 0.33–0.75) among 347 vs 359 men;
- 0.67 (95% CI = 0.46–0.98) among 372 vs 376 White patients and 0.45 (95% CI = 0.17–1.20) among 88 vs 87 patients of other race;
- 0.55 (95% CI = 0.37–0.82) among 421 vs 426 patients with an Eastern Cooperative Oncology Group performance status of 0 and 0.84 (95% CI = 0.44–1.63) among 75 vs 72 with a performance status of 1;
- 0.59 (95% CI = 0.40–0.87) among 422 vs 433 patients with M0 intermediate-to-high-risk disease and 0.78 (95% CI = 0.32–1.93) among 40 vs 37 with M0 high-risk disease.
The disease-free survival benefit with pembrolizumab was consistent with that 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 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 treatment, and 92.4% vs 84.8% received VEGF- or VEGFR-targeted therapy.
Adverse Events
The safety analysis was consistent with prior reports. Overall, for the pembrolizumab group vs the placebo group, treatment-related adverse events of any grade occurred in 79.1% vs 53.0% of patients, including grade 3 or 4 adverse events in 18.6% vs 1.2%. Serious adverse events occurred in 20.7% vs 11.5% of patients, and adverse events led to discontinuation of the study treatment in 21.1% vs 2.2%. A total of 10 treatment-related serious adverse events occurred in the pembrolizumab group at more than 90 days after discontinuation of the 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.”
DISCLOSURE: The study was funded by Merck Sharp and Dohme, a subsidiary of Merck. For full disclosures of the study authors, visit nejm.org.
REFERENCE
1. Choueiri TK, Tomczak P, Park SH, et al: Overall survival with adjuvant pembrolizumab in renal-cell carcinoma. N Engl J Med 390:1359-1371, 2024.
