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The FDA has approved belzutifan (Welireg) for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), CNS hemangioblastomas, or pancreatic neuroendocrine tumors (pNETS) not requiring immediate surgery.1
The approval was based on data from the phase 2 Study 004, which enrolled patients with VHL-associated RCC, as well as non-renal lesions. Belzutifan induced an objective response rate (ORR) of 49% (n = 30) among 61 patients with VHL-associated RCC. All responses were partial responses.
The median duration of response (DOR) was not reached (range, 2.8+ months to 22+ months). Seventeen responders (56%) had a DOR of at least 1 year. The median time to response was 8 months (range 2.7-19).
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 solid tumor localized to the kidney, 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, 24 patients had CNS hemangioblastomas, and 12 patients had pNETs.
Clinical activity with belzutifan was observed in non-RCC lesions. The ORR in pNETS was 83% (n = 10), including 2 complete responses and 8 partial responses. In CNS hemangioblastomas, the ORR was 63% (n = 15), including 1 complete response and 14 partial responses. The median DOR was not reached in either subgroup. The rate of patients with a DOR ≥12 months was 73% and 50% in the CNS hemangioblastomas and pNETS subgroups, respectively.
The safety analysis included all 61 patients. The most common adverse events (AEs) across all grades were anemia (90%), fatigue (64%), headache (39%), dizziness (38%), nausea (31%), constipation (13%), abdominal pain (13%), visual impairment (21%), upper respiratory tract infection (21%), dyspnea (20%), arthralgia (18%), myalgia (16%), hypertension (13%), and increased weight (12%).
Grade 3/4 AEs included anemia (7%), fatigue (5%), hypertension (3.3%) visual impairment (3.3%), dyspnea (1.6%), and increased weight (1.6%).
The FDA noted in a press release, “The use of erythropoiesis stimulating agents for treatment of anemia is not recommended in patients treated with belzutifan.”
1. FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. Published online August 13, 2021. Accessed August 13, 2021. https://bit.ly/3fY5JEw.