Salvage Therapy for Advanced Clear-Cell Renal Cancer

For patients with progressive, metastatic clear-cell renal cancer after treatment with immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor–tyrosine kinase inhibitors (VEGFR-TKIs), effective management options are limited. Alteration of the VHL gene occurs in the majority of clear-cell renal cancers and is associated with dysregulation of the hypoxia-inducible factor (HIF) pathway as a consequence of accumulation of HIF-2α. Belzutifan is a small-molecule inhibitor of HIF-2α with demonstrated activity in clear-cell renal cancer.

In this industry-sponsored, phase 3 trial, 746 patients with advanced clear-cell renal cancer previously treated with ICIs and antiangiogenic agents were randomized to receive either belzutifan (120 mg daily) or everolimus (10 mg daily). The dual primary endpoints were progression-free survival (PFS) and overall survival (OS).

Most patients (86%) had received two or three previous lines of therapy. At a median follow-up of 18.4 months, although the median PFS was 5.6 months in both arms, significantly more patients in the belzutifan arm than the everolimus arm were alive and free of progression (24% vs. 8.3%; P=0.002). At a median follow-up of 25.7 months, the median OS did not differ significantly between arms (21.4 and 18.1 months, respectively; hazard ratio for death, 0.88).

The incidence of grade 3–5 adverse events was approximately 62% in both arms. Adverse events led to treatment interruption in 43.5% of patients in the belzutifan group and 48.1% in the everolimus group.