Belzutifan Shows Activity in Patients With von Hippel-Lindau Disease–Associated Renal Cell Carcinoma

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In the phase II MK-6482-004 trial reported in The New England Journal of Medicine, Eric Jonasch, MD, and colleagues found that the hypoxia-inducible factor (HIF)-2α inhibitor belzutifan produced responses in patients with renal cell carcinoma (RCC) associated with von Hippel-Lindau disease. Responses were also observed in non-RCC neoplasms in these patients.

A stated by the investigators, “Patients with von Hippel-Lindau disease have a high incidence of RCC owing to VHL gene inactivation and constitutive activation of the transcription factor HIF-2α.”

Eric Jonasch, MD

Eric Jonasch, MD

Study Details

In the trial, 61 patients with RCC were enrolled between May 2018 and March 2019 from sites in the United States, Denmark, France, and the United Kingdom. Patients received oral belzutifan at 120 mg once daily until disease progression or unacceptable toxicity.

The primary endpoint was objective response of RCC assessed by independent central radiology review committee. Responses in non-RCC neoplasms in the patients were also assessed.


Median follow-up was 21.8 months (range = 20.2–30.1 months). Objective responses (all partial) were observed in 30 patients with RCC (49%, 95% confidence interval [CI] = 36%–62%). An additional 30 patients (49%) had stable disease. Median duration of response was not reached (range = 2.8+ to 22.3+ months), with all responders continuing to receive treatment as of data cutoff in December 2020. Progression-free survival at 24 months was 96% (95% CI = 87%–99%).

All 61 patients had pancreatic lesions; objective response was observed in 47 (77%), including complete response in 6 (10%). Among 22 patients with pancreatic neuroendocrine tumors, objective response was observed in 20 (91%), with complete response in 3 (14%). Among 50 patients with central nervous system hemangioblastomas, 15 (30%) had objective response, including complete response in 3 (6%). Among the 16 eyes evaluated in 12 patients with retinal hemangioblastomas, all (100%) were graded as improved.


  • The objective response rate in patients with RCC was 49%, with median duration of response not being reached.
  • Progression-free survival at 24 months was 96%.

Adverse Events

Adverse events were generally grade 1 or 2. The most common adverse events of any grade were anemia (90%), fatigue (66%), headache (41%), dizziness (39%), nausea (34%), and dyspnea (23%). Grade 3 or 4 adverse events occurred in 20 patients (33%), the most common being anemia (8%), hypertension (8%), and fatigue (5%); only one grade 4 event was observed (retinal detachment).

Adverse events led to treatment interruption in 43% of patients and dose reduction in 15%. Treatment was discontinued in seven patients, due to voluntary discontinuation in four, treatment-related grade 1 dizziness in one, disease progression in one, and death due to fentanyl toxicity in one.

The investigators concluded, “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.”

Disclosure: The study was funded by Merck Sharp and Dohme and others. For full disclosures of the study authors, visit

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