BACKGROUND: Patients with von Hippel-Lindau (VHL) disease have a high incidence 
of renal cell carcinoma owing to VHL gene inactivation and constitutive 
activation of the transcription factor hypoxia-inducible factor 2α (HIF-2α).
METHODS: In this phase 2, open-label, single-group trial, we investigated the 
efficacy and safety of the HIF-2α inhibitor belzutifan (MK-6482, previously 
called PT2977), administered orally at a dose of 120 mg daily, in patients with 
renal cell carcinoma associated with VHL disease. The primary end point was 
objective response (complete or partial response) as measured according to the 
Response Evaluation Criteria in Solid Tumors, version 1.1, by an independent 
central radiology review committee. We also assessed responses to belzutifan in 
patients with non-renal cell carcinoma neoplasms and the safety of belzutifan.
RESULTS: After a median follow-up of 21.8 months (range, 20.2 to 30.1), the 
percentage of patients with renal cell carcinoma who had an objective response 
was 49% (95% confidence interval, 36 to 62). Responses were also observed in 
patients with pancreatic lesions (47 of 61 patients [77%]) and central nervous 
system hemangioblastomas (15 of 50 patients [30%]). Among the 16 eyes that could 
be evaluated in 12 patients with retinal hemangioblastomas at baseline, all 
(100%) were graded as showing improvement. The most common adverse events were 
anemia (in 90% of the patients) and fatigue (in 66%). Seven patients 
discontinued treatment: four patients voluntarily discontinued, one discontinued 
owing to a treatment-related adverse event (grade 1 dizziness), one discontinued 
because of disease progression as assessed by the investigator, and one patient 
died (of acute toxic effects of fentanyl).
CONCLUSIONS: Belzutifan was associated with predominantly grade 1 and 2 adverse 
events and showed activity in patients with renal cell carcinomas and non-renal 
cell carcinoma neoplasms associated with VHL disease. (Funded by Merck Sharp and 
Dohme and others; MK-6482-004 ClinicalTrials.gov number, NCT03401788.).