Background
Randomised, double-blind, placebo-controlled phase 3 trial of adjuvant pembrolizumab after nephrectomy in clear cell renal cell carcinoma (ccRCC) at increased risk of recurrence. 994 patients randomised (pembrolizumab n=496, placebo n=498). This report is the fourth prespecified interim analysis, with a minimum 5-year follow-up.
Results
Interventions and follow up: Arm A: Pembrolizumab 200 mg IV every 3 weeks for ≤17 cycles (~1 year) after nephrectomy (± metastasectomy).
Arm B: Placebo every 3 weeks.
Primary endpoint: disease-free survival (DFS, investigator-assessed). Key secondary: overall survival (OS).
mFollow up: 70 months (range 60–87).
Results: DFS: HR 0.71 (95% CI 0.59–0.86); median NR vs 68 mo; 5-year DFS 60.9% vs 52.2%.
OS: HR 0.66 (95% CI 0.48–0.90); median NR in both arms; 5-year OS 87.7% vs 82.3%.
Arm B: Placebo every 3 weeks.
Primary endpoint: disease-free survival (DFS, investigator-assessed). Key secondary: overall survival (OS).
mFollow up: 70 months (range 60–87).
Results: DFS: HR 0.71 (95% CI 0.59–0.86); median NR vs 68 mo; 5-year DFS 60.9% vs 52.2%.
OS: HR 0.66 (95% CI 0.48–0.90); median NR in both arms; 5-year OS 87.7% vs 82.3%.
Adverse events
Grade 3–5 (all-cause): 32.4% vs 17.7%.
Treatment-related grade 3/4: 18.6% vs 1.2%.
Serious AEs (any cause): 20.7% vs 11.5%.
Immune-mediated: hypothyroidism and other irAEs predominated; no treatment-related deaths.
Treatment-related grade 3/4: 18.6% vs 1.2%.
Serious AEs (any cause): 20.7% vs 11.5%.
Immune-mediated: hypothyroidism and other irAEs predominated; no treatment-related deaths.
Conclusions
At 5 years, adjuvant pembrolizumab maintained significant, clinically meaningful improvements in both DFS (HR 0.71) and OS (HR 0.66) versus placebo, with no new safety signals. These mature data solidify adjuvant pembrolizumab as a standard of care for high-risk ccRCC after nephrectomy.
Key Limitations
Placebo-controlled with no active adjuvant comparator (other adjuvant checkpoint-inhibitor trials were negative); DFS remains investigator-assessed. Roughly 1 in 8 placebo patients remained recurrence-free long-term, and no biomarker identifies who truly benefits; late immune-related toxicity and quality-of-life trade-offs persist.
Clinical Context
KEYNOTE-564 is the basis for FDA (2021) and EMA approval of adjuvant pembrolizumab in high-risk ccRCC and is NCCN category 1 / ESMO-preferred — the only adjuvant therapy in RCC with a demonstrated OS benefit (adjuvant atezolizumab [IMmotion010] and nivolumab-based regimens were negative). The 5-year data reinforce this position. NCT03142334.