The identification of the VHL gene and its role in regulating the hypoxia-inducible factor signaling pathway has helped to revolutionize the treatment of renal cell carcinoma (RCC). Belzutifan is a novel small-molecule inhibitor of hypoxia-inducible factor 2α which has demonstrated efficacy in treating von Hippel-Lindau (VHL) disease, earning regulatory approvals for this indication. There is also early evidence for efficacy in sporadic RCC. Belzutifan has a favorable safety profile. Several clinical trials are currently ongoing, which should help in identifying this promising drug's role in RCC and beyond. This review summarizes the history, pharmacology and clinical evidence for belzutifan use to date, and also explores unanswered questions as they relate to this novel therapeutic agent.
Keywords: HIF-2α inhibitor; belzutifan; hemangioblastomas; kidney cancer; pancreatic neuroendocrine tumors; renal cancer; renal cell carcinoma; systemic therapy; von Hippel–Lindau disease.
The novel drug belzutifan was developed after years of research in identifying the VHL gene and how genetic abnormalities in VHL may result in tumor growth. Belzutifan has been approved for use in patients with VHL disease – a rare familial disorder first described in the 19th century that presents with a variety of cancerous and noncancerous tumors, including kidney cancer. Growing evidence supports belzutifan’s use in non-familial kidney cancer as well. This is important because most patients eventually develop resistance to the currently available cancer treatments, highlighting the need for drugs with a different mechanism of action. Belzutifan works by blocking a protein called HIF-2a, which causes tumor growth in patients with VHL disease. Belzutifan is well tolerated, with the most common side effects being low energy, hemoglobin and blood oxygen. This review summarizes the history, mechanism of action and research evidence to date supporting the use of belzutifan in VHL disease and cancer treatment. We also discuss future directions, including remaining clinical questions and areas of ongoing research.