Belzutifan (HIF-2α inhibitor) Delivers 6-Year, Surgery-Sparing Control in VHL RCC/CNS HB/pNET

Belzutifan is an oral, potent hypoxia-inducible factor 2α (HIF-2α) inhibitor evaluated in the open-label, single-arm Phase 2 LITESPARK-004 study (NCT03401788) for germline VHL patients with nonmetastatic RCC not requiring immediate surgery (no lesion >3cm), plus VHL-associated CNS hemangioblastomas (HB) and pNETs (n=61 treated; median follow-up 73.8 months; data cutoff April 1, 2025). IRC-assessed ORR was 70% in RCC (8 CR/35 PR), 52% in CNS HB (7 CR/19 PR), and 91% in pNETs (14 CR/6 PR); median DOR and median PFS were not reached across tumor types with 48-month PFS rates of 79% (RCC), 80% (CNS HB), and 90% (pNET), and retinal HBs improved in 100% of affected eyes (18/18). Clinically, tumor-reduction procedures dropped from 75% of patients in the 5 years pre-belzutifan to 36% after starting therapy (including procedures after discontinuation), aligning with the VHL “3cm rule” surveillance paradigm where lesions >3cm typically trigger nephron-sparing intervention; Grade 3 TRAEs occurred in 20% (most commonly anemia 11%), with no Grade 4/5 TRAEs and no new TRAE-driven discontinuations reported with extended follow-up.