Targeting HIF-2 Alpha in Renal Cell Carcinoma

Opinion StatementCurrent treatment options for patients with metastatic renal cell carcinoma (mRCC) are limited to immunotherapy with checkpoint inhibitors and targeted therapies that inhibit the vascular endothelial growth factor receptors (VEFG-R) and the mammalian target of rapamycin (mTOR). Despite significantly improved outcomes over the last few decades, most patients with mRCC will ultimately develop resistance to these therapies, thus highlighting the critical need for novel treatment options. As part of the VHL-HIF-VEGF axis that rests at the foundation of RCC pathogenesis, hypoxia-inducible factor 2 alpha (HIF-2 alpha) has been identified as a rationale target for mRCC treatment. Indeed, one such agent (belzutifan) is already approved for VHL-associated RCC and other VHL-associated neoplasms. Early trials of belzutifan indicate encouraging efficacy and good tolerability in sporadic mRCC as well. The potential inclusion of belzutifan and other HIF-2 alpha inhibitors into the mRCC treatment armamentarium either as a single agent or as combination therapy would be a welcome addition for patients with mRCC.

Automated summary

Current treatment options for mRCC are limited, but HIF-2 alpha inhibitors, such as belzutifan, show promising efficacy and tolerability. Inclusion of these inhibitors in mRCC treatment as single agents or in combination therapy would be welcomed.