Pembrolizumab + belzutifan (HIF-2α) improves adjuvant DFS in high-risk ccRCC—at a clear G3+ toxicity cost

Pembrolizumab is a PD-1 antibody and belzutifan is an oral hypoxia-inducible factor-2α (HIF-2α) inhibitor; in LITESPARK-022 (Phase 3, double-blind; NCT05239728), patients with resected clear-cell RCC at increased recurrence risk received pembrolizumab 400mg IV q6w (≤9 doses) plus belzutifan 120mg daily vs pembrolizumab plus placebo for ~1 year (n=1841). At data cutoff August 23, 2025 (median follow-up 28.4 months), DFS favored the combo (HR 0.72, 95% CI 0.59–0.87; p<0.001), with 24-mo DFS 80.7% vs 73.7%—an absolute +7.0% gain vs the current adjuvant backbone of pembrolizumab alone (KEYNOTE-564 established pembro vs placebo at ~24-mo DFS 77.3% vs 68.1%, i.e., pembrolizumab is already a meaningful step up from observation). OS is immature (29% of final events) and not yet different (HR 0.78; p=0.24; 24-mo OS 96.2% vs 95.7%); importantly, grade ≥3 AEs were much higher with belzutifan (52.1% vs 30.2%), raising the bar for patient selection and tolerability in a curative-intent setting.