Background
Phase III, double-blind, randomized adjuvant trial in clear cell renal cell carcinoma (ccRCC) at increased risk of recurrence after nephrectomy (stage M0 intermediate-high/high risk, or M1 with no evidence of disease post-metastasectomy). Adds the oral HIF-2α inhibitor belzutifan to standard adjuvant pembrolizumab. First adjuvant phase III RCC trial to show benefit for a combination over an active immunotherapy comparator. Reported at ASCO GU 2026.
Interventions and follow up
Arm A: Pembrolizumab 400 mg IV Q6W (~1 year, 9 doses) + belzutifan 120 mg orally once daily
Arm B: Pembrolizumab 400 mg IV Q6W + placebo
Primary endpoint: Disease-free survival (DFS)
Median follow up: ~1 year at interim analysis
Arm B: Pembrolizumab 400 mg IV Q6W + placebo
Primary endpoint: Disease-free survival (DFS)
Median follow up: ~1 year at interim analysis
Results
Disease-free survival: 28% reduction in risk of recurrence or death with pembrolizumab + belzutifan vs pembrolizumab alone
Comparator: First adjuvant RCC combination to show significant DFS benefit over an active immunotherapy control
Overall survival: Immature; not yet reported
Comparator: First adjuvant RCC combination to show significant DFS benefit over an active immunotherapy control
Overall survival: Immature; not yet reported
Adverse events
Grade ≥3 AE: 52.5% (pembrolizumab + belzutifan) vs 30.2% (pembrolizumab alone)
Belzutifan class effects: Anemia and hypoxia (on-target HIF-2α effects) requiring monitoring; fatigue and nausea also reported
Belzutifan class effects: Anemia and hypoxia (on-target HIF-2α effects) requiring monitoring; fatigue and nausea also reported
Conclusions
Adding belzutifan to adjuvant pembrolizumab significantly improved disease-free survival in resected high-risk ccRCC, supporting HIF-2α inhibition as a complementary mechanism to immunotherapy in the adjuvant setting, at the cost of increased grade ≥3 toxicity.
Key Limitations
Interim analysis with short (~1 year) follow-up; overall survival benefit not yet demonstrated. Higher grade ≥3 toxicity (52.5% vs 30.2%) raises tolerability and discontinuation concerns in an adjuvant population. Long-term durability and patient selection remain to be defined.
Clinical Context
Belzutifan is already FDA-approved for VHL-associated tumors and advanced sporadic ccRCC (after IO and VEGF-TKI). LITESPARK-022 positions HIF-2α inhibition as a novel non-VEGF-TKI axis in the adjuvant space, building on adjuvant pembrolizumab (KEYNOTE-564). Integration with existing adjuvant immunotherapy standards and ESMO guidance is evolving pending mature OS data.