On August 13, the U.S. Food and Drug Administration (FDA) approved belzutifan (Welireg), a hypoxia-inducible factor inhibitor, for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNETs) not requiring immediate surgery.
Study 004
Belzutifan was investigated in the ongoing Study 004 (ClinicalTrials.gov identifier NCT03401788), an open-label clinical trial in 61 patients with VHL-associated RCC (VHL-RCC) diagnosed based on a VHL germline alteration and with at least one measurable solid tumor localized to the kidney. Enrolled patients had other VHL-associated tumors, including CNS hemangioblastomas and pNETs.
Patients received belzutifan at 120 mg once daily until disease progression or unacceptable toxicity. The primary efficacy endpoint was overall response rate measured by radiology assessment, as assessed by an independent review committee using Response Evaluation Criteria in Solid Tumors version 1.1. Additional efficacy endpoints included duration of response and time to response.
An overall response rate of 49% (95% confidence interval [CI] = 36%–62%) was reported in patients with VHL-associated RCC. All patients with VHL-RCC with a response were followed for a minimum of 18 months from the start of treatment. The median duration of response was not reached; 56% of responders had a duration of response of 12 months or longer, and a median time to response of 8 months. In patients with other VHL-associated non-RCC tumors, 24 patients with measurable CNS hemangioblastomas had an overall response rate of 63%, and 12 patients with measurable pNETs had an overall response rate of 83%. Median duration of response was not reached, with 73% and 50% of patients having response durations of 12 months or longer for CNS hemangioblastomas and pNETs, respectively.
The most common adverse reactions, including laboratory abnormalities, reported in ≥ 20% of patients who received belzutifan were decreased hemoglobin, anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Anemia and hypoxia from belzutifan use can be severe.
In Study 004, anemia occurred in 90% of patients, and 7% had grade 3 anemia. Patients should be transfused as clinically indicated. The use of erythropoiesis-stimulating agents for treatment of anemia is not recommended in patients treated with belzutifan. In Study 004, hypoxia occurred in 1.6% of patients. Belzutifan can render some hormonal contraceptives ineffective, and belzutifan exposure during pregnancy can cause embryofetal harm.
The recommended belzutifan dosage is 120 mg administered orally once daily with or without food.
