The Clinical Role of Hypoxia Inducible Factor (HIF) Inhibition in Renal Cancer: A Focus on Belzutifan

Systemic therapy for metastatic Renal Cell Carcinoma (mRCC) has dramatically improved in the last years because of the use of immunotherapy with checkpoint inhibitor combinations with or without targeted therapies against the Vascular Endothelial Growth Factor Receptors (VEGFR). As a result, patients with mRCC have prolonged survival time, but they ultimately develop resistance and the disease progresses, which highlights the critical need for novel treatment options. The Hypoxia-inducible Factor (HIF) pathway is central to the pathophysiology of ccRCC and von Hippel-Lindau (VHL) disease. As part of the VHL-HIF-VEGF axis, the HIF-2α inhibition has been identified as a rationale target for mRCC treatment. Indeed, one such agent called belzutifan is already approved for VHL-associated RCC and other VHLassociated neoplasms, and a series of trials have indicated encouraging efficacy and good tolerability in sporadic mRCC as well. The potential inclusion of belzutifan into the mRCC treatment armamentarium either as a single agent or as combination therapy could cover the lack of therapeutic options as well as the need for a new combination in mRCC; therefore, this drug has the potential to be largely used in mRCC. In this review, we have recapitulated the clinical data supporting the use of belzutifan in mRCC as monotherapy and the background for combination with other agents as well as its safety profile.