On August 13, 2021, the FDA approved belzutifan (Welireg; Merck), an oral hypoxia-inducible factor inhibitor, for the treatment of adults with von Hippel-Lindau (VHL) disease that is associated with 1 of 3 tumor types that are not requiring immediate surgery, including renal-cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET).
The FDA approved belzutifan based on the ongoing Study 004, an open-label clinical trial involving 61 patients with VHL-associated RCC diagnosed based on a VHL germline alteration and at least 1 measurable solid tumor localized to the kidney; in addition, 24 patients had VHL-associated CNS hemangioblastomas and 12 patients had pNET. All the patients received belzutifan 120 mg once daily until disease progression or unacceptable adverse events.
The primary end point was overall response rate (ORR). The secondary end points included duration of response (DOR) and time to response.
The ORR was 49% (95% confidence interval [CI], 36%-62%) among patients with VHL-associated RCC. The patients who had a response were followed for ≥18 months. The median DOR was not reached, and 56% of responders had a response lasting ≥12 months, with a median time to response of 8 months. Furthermore, the ORR was 63% in the 24 patients with VHL-associated CNS hemangioblastomas, and 83% in the 12 patients with VHL-associated pNET. The median DOR among these 2 cohorts was not reached; 73% and 50% of patients, respectively, had a response lasting ≥12 months.
The most common (≥20%) adverse reactions with belzutifan were decreased hemoglobin level, anemia, fatigue, increased creatinine, headache, dizziness, increased glucose level, and nausea. Anemia and hypoxia linked to belzutifan use can be severe. Anemia occurred in 90% of the patients, including 7% grade 3 anemia.