FDA grants priority review to belzutifan for VHL-associated RCC

March 16, 2021
Jason M. Broderick

The FDA has granted a priority review designation to a new drug application (NDA) for the HIF-2α inhibitor belzutifan (MK-6482) for the treatment of patients with Von Hippel-Lindau (VHL)-associated renal cell carcinoma (RCC), not requiring immediate surgery.1

The NDA is supported by data from the phase 2 Study-004 trial,2 which enrolled patients with VHL-associated RCC, as well as non-renal lesions. The findings showed that at a median follow-up of 68.7 weeks (range, 18.3-104.7), belzutifan induced an objective response rate (ORR) of 36.1% in RCC lesions among 61 patients. The ORR comprised 22 confirmed partial responses (PRs). There were also 7 unconfirmed PRs. Overall, 91.8% (n = 56) of patients had at least some decrease in the size of target lesions.

The median time to response in renal tumors was 31 weeks, although responses were observed as long as 62 weeks after the start of therapy. The median duration of response had not yet been reached and the progression-free survival rate at 52 weeks was 98.3%.

Thirty-eight (62.3%) patients reached stable disease, 1 patient was not evaluable for response, and 0 patients had progressive disease.

The FDA is scheduled to decide on the NDA on or before September 15, 2021.

“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, clinical research, Merck Research Laboratories, stated 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,” added Ebbinghaus.

Key eligibility criteria for the open-label phase 2 study (NCT03401788) included a confirmed diagnosis of VHL disease (based on germline mutation), at least 1 measurable RCC tumor, and an ECOG performance status of 0 or 1. Prior systemic anticancer therapy was not allowed and patients with metastatic disease were excluded from enrollment.

Overall, the study included 61 patients with a median age of 41 years (range, 19-66). Thirty-two (52.5%) patients were male, and 29 (47.5%) were female. Fifty patients had an ECOG performance status of 0, 10 patients had a performance status of 1, and 1 patient had a performance status of 2. In addition to renal tumors, all 61 patients had pancreatic lesions, 43 patients had brain hemangioblastomas, and 16 patients had retinal lesions.

Patients received 120 mg of oral belzutifan once daily. Tumors were evaluated at initial screening and then every 12 weeks. The primary end point was ORR by central review, with secondary end points including ORR in non-RCC lesions, duration of response in RCC and non-RCC lesions, and safety.

At a minimum follow-up of 60 weeks, 56 (91.8%) patients remained on treatment.

Clinical activity with belzutifan was observed in non-RCC lesions. The confirmed ORR in pancreatic lesions was 63.9%, including 4 complete responses. The confirmed ORR in brain hemangioblastomas was 30.2%, with a CR rate of 11.6%. Also, 11 (68.8%) of 15 patients with retinal lesions demonstrated improvement in these lesions, with the 4 other patients reaching stable disease.

Safety data showed that 60 of the 61 patients had at least 1 treatment-related adverse event (TRAE). The most common all-cause AE was grade 1/2 anemia, occurring in 51 (83.6%) patients. Eight (13.1%) patients had a grade 3 TRAE. Four (6.6%) patients had grade 3 anemia.

There were no grade 4/5 TRAEs. There was 1 discontinuation due to a TRAE (grade 1 dizziness).


1. Merck Receives Priority Review From FDA for New Drug Application for HIF-2α Inhibitor Belzutifan (MK-6482). Published online March 16, 2021. Accessed March 16, 2021. https://bit.ly/3vvz7Ib.

2. Srinivasan R, Donskov F, IIiopoulos O, et al. Oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau (VHL) disease–associated clear cell renal cell carcinoma: evaluation of RCC and non-RCC disease. 2020 Society of Urologic Oncology Annual Meeting (virtual). December 3-5, 2020. Abstract 10.