Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease

N Engl J Med. 2021 Nov 25;385(22):2036-2046. doi: 10.1056/NEJMoa2103425.


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 number, NCT03401788.).

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Age of Onset
  • Aged
  • Anemia / chemically induced
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors*
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / etiology
  • Disease Progression
  • Fatigue / chemically induced
  • Female
  • Follow-Up Studies
  • Hemangioblastoma / drug therapy
  • Humans
  • Indenes / adverse effects
  • Indenes / therapeutic use*
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / etiology
  • Male
  • Middle Aged
  • Neoplasms, Multiple Primary / drug therapy
  • Neuroendocrine Tumors / drug therapy
  • Pancreatic Neoplasms / drug therapy
  • von Hippel-Lindau Disease / complications*
  • von Hippel-Lindau Disease / genetics


  • Antineoplastic Agents
  • Basic Helix-Loop-Helix Transcription Factors
  • Indenes
  • belzutifan

Associated data