Targeting HIF-2α: the role of belzutifan in clear cell renal carcinoma management

INTRODUCTION: Belzutifan is a first-in-class hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor. It targets the von Hippel-Lindau protein (pVHL)-HIF-vascular endothelial growth factor (VEGF) pathway, which is crucial in cellular responses to hypoxia. By inhibiting HIF-2α, belzutifan disrupts the transcription of genes involved in tumor growth and angiogenesis. AREAS COVERED: In this review, we describe the pVHL-HIF-VEGF pathway and how it led to the development of HIF inhibitors, including belzutifan. A search was conducted for trials involving Belzutifan, including phase I-III trials. We describe the relevant toxicity, with emphasis on hypoxia and anemia. EXPERT OPINION: Belzutifan is a relatively safe drug, with manageable adverse events, including anemia and hypoxia as on-target toxicity. Ongoing trials are studying its benefit in overall survival for RCC in first-line treatment and its potential in other malignancies. The LITESPARK-005 trial reported the benefit of belzutifan in progression-free survival (PFS) compared to everolimus in later lines of treatment, with improvement in quality-of-life outcomes. Given its different mechanism of action to currently available treatments, belzutifan is expected to play a prominent role in the treatment of clear cell renal carcinoma and other cancers.