Novel Approaches with HIF-2 Targeted Therapies in Metastatic Renal Cell Carcinoma

Germline inactivation of the Von Hippel-Lindau (VHL) tumor suppressor is the defining hallmark in hereditary VHL disease and VHL-associated renal cell carcinoma (RCC). However, somatic VHL mutations are also observed in patients with sporadic RCC. Loss of function VHL mutations result in constitutive activation of hypoxia-inducible factor-2 alpha (HIF-2 alpha), which leads to increased expression of HIF target genes that promote angiogenesis and tumor growth. As of 2023, belzutifan is currently the only approved HIF-2 alpha inhibitor for both VHL-associated and sporadic metastatic RCC (mRCC). However, there is potential for resistance with HIF-2 alpha inhibitors which warrants novel HIF-2 alpha-targeting strategies. In this review, we discuss the potential resistance mechanisms with belzutifan and current clinical trials evaluating novel combinations of belzutifan with other targeted therapies and immune checkpoint inhibitors which may enhance the efficacy of HIF-2 alpha targeting. Lastly, we also discuss newer generation HIF-2 alpha inhibitors that are currently under early investigation and outline future directions and challenges with HIF-2 alpha inhibitors for mRCC.