Belzutifan (HIF-2α inhibitor) + Lenvatinib (VEGFR TKI) Extends PFS vs Cabozantinib in Post–PD-(L)1 ccRCC (LITESPARK-011)

Belzutifan is an oral HIF-2α inhibitor and lenvatinib is an oral multikinase VEGFR TKI; this open-label Phase 3 trial (LITESPARK-011; NCT04586231) randomized previously treated advanced clear-cell RCC after anti–PD-1/PD-L1 (± prior VEGFR TKI) to belzutifan 120mg + lenvatinib 20mg daily (n=371) vs cabozantinib 60mg daily (n=376). At the second interim analysis (data cutoff April 9, 2025; median follow-up 29.0 months), median PFS by masked independent central review was 14.8 vs 10.7 months (HR 0.70, one-sided p<0.0001), while OS was not statistically significant: 34.9 vs 27.6 months (HR 0.85, one-sided p=0.061). Grade ≥3 TEAEs were similar (84% vs 83%) with hypertension the most common (31% vs 29%); treatment-related AEs led to 2 deaths on belzutifan-lenvatinib vs 1 on cabozantinib—netting a PFS gain over a common post-ICI benchmark (cabozantinib in METEOR: mPFS 7.4 months vs everolimus, with typical real-world post-ICI PFS often in the high-single-digit/low-double-digit range).