Belzutifan monotherapy and combination therapies in renal cell carcinoma: a clinical trial perspective from the ARON working group

Introduction: Several studies have identified Hypoxia-Inducible Factor 2-alpha (HIF-2α) as a key oncogenic driver in clear cell renal cell carcinoma (ccRCC). In this context, belzutifan emerges as an oral inhibitor of HIF-2α, that acts by blocking the heterodimerization of HIF-2α with HIF-1β, thereby preventing the transcription of hypoxia-target genes and reducing VEGF-mediated tumor growth. The LITESPARK series of studies recently defined the emerging role of belzutifan in the therapeutic landscape of RCC, and further studies are ongoing. Areas covered: In the current review, we discuss the role of belzutifan as an innovative and promising therapeutic strategy for targeting a key biological mechanism in ccRCC. Expert opinion: According to available evidence and data, belzutifan has generally been well tolerated, though anemia is a frequent on-target side effect and, along with hypoxia, necessitates monitoring throughout treatment. As reported, ongoing phase III clinical trials are set to yield potentially practice-changing results, investigating innovative combinatorial strategies including belzutifan. Ongoing advancement of predictive biomarkers and understanding of resistance mechanisms could improve patient selection and identify new drug targets, thereby increasing the clinical efficacy of belzutifan.