Successful Targeting of Somatic VHL Alterations With Belzutifan in Two Cases

Abstract

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.

Keywords: HIF; HIF-2α; VHL alterations; belzutifan; renal cell carcinoma.

Figure 1

Depicts the timeline and clinical course of case 1.

Figure 2

CAT scans showing antitumor response in three index lesions. Yellow circles mark the site of the lesion. Upper panel demonstrates a right (Rt) subdiaphragmatic nodule, which regressed significantly after the initiation of belzutifan. Lower panel shows a Rt upper quadrant lesion and left (Lt) upper quadrant nodule. Complete resolution of the Lt upper quadrant peritoneal lesion in the imaging obtained in August 2023 is shown. Best response is a partial response with 67% decrease in total target lesions compared with baseline.

Figure 3

Depicts the clinical course and timeline for Case 2. Cabo: cabozantinib; GKRS: gamma knife radiosurgery; Ipi: ipilimumab; Nivo: nivolumab; VATS: video-assisted thoracoscopic surgery.

Figure 4

Shows consecutive imaging with antitumor response in two index lesions. Yellow circles mark the site of the lesion. Upper panel demonstrates a hepatic segment 4A lesion, which responded well after initiation of personalized treatment (belzutifan + everolimus followed by belzutifan + olaparib). Lower panel shows a right kidney lesion, which entirely resolved after 6–7 months of systemic treatment. The best response is a partial response with a 63% decrease in sum target lesions.