FDA Grants Priority Review to Belzutifan for von Hippel-Lindau Disease–Associated RCC


The FDA accepted a new drug application for belzutifan to treat von Hippel-Lindau disease¬–associated renal cell carcinoma and granted it priority review based on response rate results from a phase 2 trial.

A new drug application for belzutifan was accepted by the FDA and granted priority review for the treatment of patients with von Hippel-Lindau (VHL) disease­–associated renal cell carcinoma (RCC), not requiring immediate surgery, according to Merck who is responsible for developing the agent.1

Belzutifan is a novel and potent selective inhibitor of hypoxia-inducible factor-2 alpha (HIF-2α). Proteins with hypoxia-inducible factors are known to accumulate in patients with VHL and if not properly regulated, could stimulate oncogene associated with mechanisms of malignancy.

“Von Hippel-Lindau disease is a rare genetic condition for which there is no systemic treatment option available and is associated with a high risk of cancer development in multiple organs. In fact, up to 70% of patients with VHL develop renal cell carcinoma during their lifetime,” Scot Ebbinghaus, MD, vice president of clinical research at Merck Research Laboratories, said in a press release. “This priority review validates the important progress we have made to expand and diversify Merck’s oncology pipeline with innovative, new therapeutic approaches. We look forward to working closely with the FDA to bring belzutifan to patients in need.”

The application is based on results of a phase 2 trial, Study-004 (NCT03401788), of belzutifan in the treatment of VHL disease–associated RCC, with a primary end point of objective response rate and secondary measures of disease control rate, duration of response, time to response, progression-free survival, time to surgery, and safety. Patients treated on the trial must have had at least 1 measurable solid tumor localized to the kidneys and were not in need of immediate surgical intervention.

The confirmed overall response rate (ORR) reported during the 2021 Genitourinary Cancer Symposium was 36.1% (95% CI, 24.2%-49.4%) in a cohort of 61 patients, comprised of all partial responses. In addition, 62.3% of patients had stable disease. In total, 91.8% saw a reduction in the size of the target lesion.2

Responses in pancreatic lesions (n = 61) and central nervous system (CNS) hemangioblastomas (n = 50) were also reported, with ORRs of 63.9% (95% CI, 50.6%-75.8%) and 32.0% (95% CI, 19.5%-46.7%), respectively. Corresponding rates of complete response were 6.6% and 2.0%.

The median time to response was 31.1 weeks (range, 11.6-61.0) and the median duration of response was not reached (range, 11.9-62.3). The rate of progression-free survival was 52 weeks was 98.3%.

Every patient in the cohort experience at least 1 any-grade adverse events (AE), with 98.4% of patients having at least 1 any-grade treatment-related AE (TRAE). The most common events noted in at least 30% of the patient population were anemia (90.2%), fatigue (60.7%), headache (37.7%), dizziness (36.1%), and nausea (31.1%).

Grade 3 or greater AEs occurred in 24.6% of cohort, with anemia (6.6%) and fatigue (4.9%) being the most common. Treatment discontinuations due to an AE occurred in 2 patients (3.3%), with only 1 deemed to be resulting from a TRAE. There was 1 death in the trial that was deemed not related to a TRAE.

The FDA has set a Prescription Drug User Fee Act date of September 15, 2021.


1. Merck receives priority review from FDA for new drug application for HIF-2α inhibitor belzutifan (MK-6482). News release. Merck. March 16, 2021. Accessed March 16, 2021. https://bit.ly/3rROgBz

2. Phase II study of the oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau disease–associated renal cell carcinoma. J Clin Oncol. 2021;38(suppl 15):5003. doi:10.1200/JCO.2020.38.15_suppl.5003

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