Multinational phase 3 trial of belzutifan versus everolimus for previously treated advanced clear-cell renal cell carcinoma

Belzutifan is a hypoxia-inducible factor 2α inhibitor, with activity for clear-cell renal cell carcinoma in early-phase studies. The multinational phase 3 LITESPARK-005 trial randomized patients with advanced clear-cell renal cell carcinoma (accRCC) who had previously received immune checkpoint and antiangiogenic therapies to belzutifan (n=374) or everolimus (n=372). At 18 months, 24.0% of the patients in the belzutifan group and 8.3% of the patients in the everolimus group were alive and free of progression (two-sided p=0.002, which met the prespecified significance criterion). A confirmed objective response occurred in 21.9% of the patients in the belzutifan group and 3.5% of the patients in the everolimus group (p<0.001, which met the prespecified significance criterion). Median overall survival was 21.4 months in the belzutifan group and 18.1 months in the everolimus group (p=0.20). Grade 3 or higher adverse events of any cause occurred in 61.8% of the patients in the belzutifan group (grade 5 in 3.5%) and 62.5% in the everolimus group (grade 5 in 5.3%); adverse events leading to discontinuation occurred in 5.9% and 14.7%, respectively. The authors conclude that belzutifan showed a significant benefit over everolimus with respect to progression-free survival and objective response in accRCC patients who had previously received immune checkpoint and antiangiogenic therapies.