Background
Double-blind, placebo-controlled phase 3 trial. N=1841 with resected clear-cell renal-cell carcinoma at intermediate-high or high risk of recurrence (or with resected metastases and no evidence of disease) after nephrectomy. Belzutifan is an oral HIF-2α inhibitor; adjuvant pembrolizumab is already standard (KEYNOTE-564). Tested whether adding belzutifan to adjuvant pembrolizumab further reduces recurrence.
Results
Interventions and follow up: Arm A: Pembrolizumab 400 mg IV q6w (≤9 doses) + belzutifan 120 mg PO daily, up to 1 year
Arm B: Pembrolizumab 400 mg IV q6w + placebo, up to 1 year
Primary endpoint: Investigator-assessed disease-free survival (DFS)
mFollow up: 28.4 months
Results: DFS: HR 0.72 (95% CI 0.59–0.87), P<.001; 24-mo DFS 80.7% vs 73.7%
OS (interim, 29% of events): HR 0.78 (95% CI 0.51–1.19), P=.24; 24-mo OS 96.2% vs 95.7% (immature)
Arm B: Pembrolizumab 400 mg IV q6w + placebo, up to 1 year
Primary endpoint: Investigator-assessed disease-free survival (DFS)
mFollow up: 28.4 months
Results: DFS: HR 0.72 (95% CI 0.59–0.87), P<.001; 24-mo DFS 80.7% vs 73.7%
OS (interim, 29% of events): HR 0.78 (95% CI 0.51–1.19), P=.24; 24-mo OS 96.2% vs 95.7% (immature)
Adverse events
Grade ≥3 (any): 52.1% vs 30.2%
Belzutifan-associated: anemia, hypoxia, ALT elevation more frequent with the combination
Belzutifan-associated: anemia, hypoxia, ALT elevation more frequent with the combination
Conclusions
Adding belzutifan to adjuvant pembrolizumab significantly improved disease-free survival in high-risk resected clear-cell RCC, at the cost of substantially more grade ≥3 toxicity. Overall survival remains immature and not yet significant.
Key Limitations
DFS is a surrogate endpoint and OS data are immature (interim HR 0.78, NS). The combination roughly doubled grade ≥3 toxicity (notably anemia and hypoxia), raising quality-of-life and cost considerations for an adjuvant population. The primary DFS endpoint was investigator-assessed rather than by blinded independent review.
Clinical Context
First adjuvant regimen to improve DFS over pembrolizumab monotherapy in RCC. On 12 June 2026 the FDA approved belzutifan plus pembrolizumab for adjuvant treatment of clear-cell RCC at intermediate-high or high risk of recurrence after nephrectomy, building on KEYNOTE-564. NCCN, ASCO, and ESMO position adjuvant pembrolizumab as an option; this establishes an intensified adjuvant alternative.