FDA Approves Belzutifan for von Hippel-Lindau–Associated Cancers

Pancreatic neuroendocrine tumor.

The FDA has approved belzutifan (Welireg™, Merck), a hypoxia-inducible factor (HIF) inhibitor, for patients with von Hippel-Lindau (VHL) disease who need therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNETs), but who do not require immediate surgery.

“Inactivation of VHL leads to aberrant stabilization and accumulation of HIF-2α, which drives tumor growth. Patients with VHL disease are at risk of clear cell RCC, pNETs, and hemangioblastomas,” wrote Ramaprasad Srinivasan, MD, PhD, Head of the Molecular Cancer Therapeutics Section in the Center for Cancer Research at the National Cancer Institute, and colleagues, in their published abstract of the results of the ongoing phase 2 Study 004 (NCT03401788), on which the approval was based. “Repeated surgeries are often needed to control clear cell RCC and other VHL disease manifestations.”

The open-label clinical trial enrolled 61 patients with VHL-associated RCC. All 61 patients received belzutifan 120 mg orally once daily until disease progression, intolerable toxicity, or decision to withdraw. The primary end point was overall response rate; secondary end points included duration of response, time to response, progression-free survival, and safety.

In patients with VHL-associated RCC, belzutifan produced an overall response rate (ORR) of 49%. At a minimum follow-up of 18 months, the median duration of response was not reached; 56% of responders had a duration of response lasting at least 12 months. The median time to response was 8 months. In patients with VHL-associated non-RCC tumors, 24 patients with measurable CNS hemangioblastomas had an ORR of 63% and 12 patients with measurable pNETs had an ORR of 83%; in both patient groups, neither group achieved median duration of response, with 73% and 50% of patients having response durations lasting at least 12 months, respectively.

The most common adverse events and laboratory abnormalities, occurring in at least 20% of patients, were decreased hemoglobin, anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. In patients receiving belzutifan, adverse reactions of anemia and hypoxia can be severe; in the study, 90% of patients experienced anemia, with 7% grade 3 anemia. Patients should receive transfusions as clinically indicated; the use of erythropoiesis-stimulating agents is not recommended for the treatment of anemia. Hypoxia occurred in 1.6% of patients receiving belzutifan in Study 004.

“Belzutifan demonstrates clinical benefit and has a favorable safety profile in patients with VHL disease–associated clear cell RCC, pNETs, and hemangioblastomas,” concluded Dr. Srinivasan and colleagues in their May 2021 abstract published in the Journal of Clinical Oncology.

The recommended dose of belzutifan is 120 mg orally once daily, with or without food.

For More Information

Srinivasan R, Donskov F, Iliopoulos O, et al (2021). Phase 2 study of belzutifan (MK-6482), an oral hypoxia-inducible factor 2α (HIF-2α) inhibitor, for Von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC). J Clin Oncol (ASCO Annual Meeting Abstracts), 39(suppl_15). Abstract 4555. DOI:10.1200/JCO.2021.39.15_suppl.4555

Clinicaltrials.gov (2020). A phase 2 study of belzutifan (PT2977, MK-6482) for the treatment of von Hippel Lindau (VHL) disease-associated renal cell carcinoma (RCC) (MK-6482-004). NLM identifier: NCT03401788.

Welireg™ (belzutifan) prescribing information (2021). Merck. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215383s000lbl.pdf

US Food & Drug Administration (2021). FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-cancers-associated-von-hippel-lindau-disease

Image credit: Nephron. Licensed under CC BY-SA 4.0

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