Background
Phase 2, open-label, single-group trial. Von Hippel-Lindau (VHL) disease — a hereditary syndrome from VHL tumor-suppressor inactivation — drives constitutive HIF-2α activation, causing renal cell carcinoma (RCC), pancreatic neuroendocrine tumors (pNETs), and CNS/retinal hemangioblastomas. Belzutifan (MK-6482) is the first oral HIF-2α inhibitor. Primary cohort: 61 patients with ≥1 VHL-associated ccRCC requiring treatment; non-RCC tumors assessed as secondary endpoints. Median age 41 years.
Interventions and follow up
Regimen: Belzutifan 120 mg orally once daily continuously until progression or intolerance (n=61)
Primary endpoint: Objective response rate (ORR) in VHL-associated RCC by RECIST 1.1, independent central review
Secondary endpoints: Response in pNETs and CNS/retinal hemangioblastomas; duration of response; safety
Median follow up: 21.8 months (range 20.2–30.1)
Primary endpoint: Objective response rate (ORR) in VHL-associated RCC by RECIST 1.1, independent central review
Secondary endpoints: Response in pNETs and CNS/retinal hemangioblastomas; duration of response; safety
Median follow up: 21.8 months (range 20.2–30.1)
Results
RCC ORR: 49% (95% CI 36–62)
RCC with ≥25% tumor reduction: 79%
Pancreatic lesion response rate: 77% (47/61)
CNS hemangioblastoma ORR: 30% (15/50)
Retinal hemangioblastoma improvement: 100% (16/16 evaluable eyes)
RCC with ≥25% tumor reduction: 79%
Pancreatic lesion response rate: 77% (47/61)
CNS hemangioblastoma ORR: 30% (15/50)
Retinal hemangioblastoma improvement: 100% (16/16 evaluable eyes)
Adverse events
Hematologic: Anemia 90% any grade (on-target HIF-2α effect reducing EPO production); grade ≥3 anemia 7%
Constitutional: Fatigue 66% any grade; grade ≥3 fatigue 3%
Discontinuation/deaths: 7 discontinued (4 voluntary, 1 toxicity [grade 1 dizziness], 1 progression, 1 unrelated death [fentanyl toxicity]); predominantly grade 1–2 toxicity overall
Constitutional: Fatigue 66% any grade; grade ≥3 fatigue 3%
Discontinuation/deaths: 7 discontinued (4 voluntary, 1 toxicity [grade 1 dizziness], 1 progression, 1 unrelated death [fentanyl toxicity]); predominantly grade 1–2 toxicity overall
Conclusions
Belzutifan produced a 49% ORR in VHL-associated ccRCC and broad multi-tumor activity across pNETs (77%) and CNS/retinal hemangioblastomas (30–100%), establishing HIF-2α inhibition as a viable mechanism in VHL disease. Reducing burden across multiple simultaneous tumor types with a single oral agent is unprecedented in VHL management.
Key Limitations
Single-arm, non-randomized phase 2 with modest sample (n=61) and no comparator. Median follow-up of 21.8 months limits assessment of durability and long-term anemia management. Generalizability beyond VHL-associated ccRCC to sporadic RCC was not addressed by this cohort.
Clinical Context
LITESPARK-004 supported the August 2021 FDA approval of belzutifan for VHL-associated RCC, CNS hemangioblastomas, and pNETs not requiring immediate surgery. It offers a non-surgical, organ-sparing option in a population otherwise managed with serial resections. The HIF-2α mechanism subsequently extended to sporadic advanced RCC (LITESPARK-005) and adjuvant combinations (LITESPARK-022). ESMO recognizes belzutifan among targeted options in VHL-associated disease.