Successful Targeting of Somatic VHL Alterations With Belzutifan in Two Cases.

Clear cell renal cell carcinoma (RCC) is commonly associated with alterations in the VHL tumor suppressor gene, resulting in upregulation of hypoxia-inducible factor pathways. Immune checkpoint inhibitors and vascular endothelial growth factor inhibitors are the mainstays of systemic treatment for metastatic RCC; however, most patients encounter disease progression after the initial response. The phase 3 clinical trial LITESPARK-005-belzutifan (HIF-2α inhibitor) demonstrated improvement in progression-free survival compared with everolimus in heavily pretreated patients unselected for somatic/germline VHL alterations (an objective response rate of 23% and a median time on therapy of 7.6 months in the belzutifan cohort), resulting in U.S. FDA approval for patients with advanced RCC. Herein, we present two cases of refractory metastatic RCC (including one with brain metastases) with somatic VHL mutations who received belzutifan after discussion in the institutional Molecular Tumor Board. Both patients had an excellent clinical response (partial remissions ongoing at >12 and >20 months). Future studies should assess the merits of biomarker selection for belzutifan treatment.