On August 13, 2021, 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 (pNET), that do not require immediate surgery.
Belzutifan was investigated in an ongoing, open-label clinical trial (Study 004, NCT03401788) 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 pNET. Patients received belzutifan 120 mg once daily until disease progression or unacceptable toxicity.
The primary efficacy endpoint was overall response rate (ORR) measured by radiology assessment, as assessed by an independent review committee using response evaluation criteria in solid tumors 1.1. Additional efficacy endpoints included duration of response (DoR), and time- to- response (TTR). An ORR of 49% (95% 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 DoR was not reached; 56% of responders had DoR ≥ 12 months and a median TTR of 8 months. In patients with other VHL-associated non-RCC tumors, 24 patients with measurable CNS hemangioblastomas had an ORR of 63% and 12 patients with measurable pNET had an ORR of 83%. Median DoR was not reached, with 73% and 50% of patients having response durations ≥ 12 months for CNS hemangioblastomas and pNET, respectively.
The most common adverse reactions, including laboratory abnormalities, reported (≥ 20%) in 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 the trial, 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 receiving belzutifan. In the trial, hypoxia occurred in 1.6% of patients. Belzutifan can render some hormonal contraceptives ineffective, and belzutifan exposure during pregnancy can cause embryo-fetal harm.
The recommended belzutifan dosage is 120 mg administered orally once daily with or without food.
The review was conducted under Project Orbis, an initiative of FDA’s Oncology Center of Excellence, which provides a framework for concurrent submission and review of oncology drugs among international partners. For the review, FDA collaborated with the Australian Therapeutic Goods Administration, Health Canada, and the Medicines and Healthcare products Regulatory Agency of the United Kingdom. The application reviews are ongoing at the other regulatory agencies.
The review used the Real-Time Oncology Review pilot program, which streamlined data submission prior to the filing of the entire clinical application, as well as the Assessment Aid and the Product Quality Assessment Aid, voluntary submissions from the applicant to facilitate FDA’s assessment. FDA approved the application approximately one month ahead of FDA’s goal date.
This application was granted priority review for this indication. A description of FDA expedited programs is in the Guidance for IndustryꟷExpedited Programs for Serious ConditionsꟷDrugs and Biologics.
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