Belzutifan for Von Hippel-Lindau disease-associated renal cell carcinoma

January 2022 Cancer trials Nalinee Pandey
Kidney cancer, renal cell carcinoma, 3D illustration and light micrograph

Results of a phase-2 study published in The New England Journal of Medicine have demonstrated the efficacy of belzutifan among patients with Von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC).

VHL disease is caused due to a mutation in the VHL gene; such patients have a high incidence of RCC. Mutation of the VHL gene activates transcription factor hypoxia-inducible factor 2α (HIF-2α), causing the formation of blood vessels and accelerated tumour growth. Belzutifan is a HIF-2α inhibitor that hinders cancer growth, spread and abnormal blood vessel development. A phase-2 clinical trial was conducted to assess the efficacy of this inhibitor among patients with VHL-associated-RCC.

Phase-II study

Between May 2018 and March 2019, an open-label, single-group, phase-2 study enrolled 61 patients from sites in the United States, Denmark, France and the United Kingdom for testing the efficacy and safety of HIF-2α inhibitor belzutifan. Patients were administered daily dosages of belzutifan (120mg) orally until disease progression or unacceptable toxicity.

The study’s primary endpoint was the objective response (complete/partial) as assessed by an independent central radiology review committee.  Response in non-RCC neoplasm was also evaluated for efficacy and safety.


After a median follow up of 21.8 months (range, 20.2-30.1), 49% of patients (n=30) had objective response (all partial, 95% confidence interval [CI] = 36%–62%). Objective response was also observed in patients with pancreatic lesions (47 out of 61 patients) and central nervous system hemangioblastomas (15 out of 50 patients). Only 16 eyes could be evaluated for 12 patients with retinal hemangioblastomas. Among them, all (100%) were graded as improved.

Anemia (in 90% of patients) and fatigue (in 66%) were the two most common adverse events. Seven patients discontinued the treatment due to reasons such as voluntary discontinuation (4), treatment-related grade 1 dizziness (1), disease progression (1), and death due to fentanyl toxicity (1).


The investigators concluded that belzutifan was associated with predominantly grade 1 and 2 adverse events, and showed activity in patients with RCC and non-RCC neoplasms associated with Von Hippel-Lindau disease.


Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, et al. 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. PMID: 34818478.