Multinational phase 3 trial of belzutifan plus lenvatinib versus cabozantinib for previously treated advanced renal cell carcinoma

The phase 3 LITESPARK-011 trial, at 184 centers in 25 countries, evaluated belzutifan plus lenvatinib versus cabozantinib in participants with advanced clear-cell renal cell carcinoma (ccRCC) previously treated with immune checkpoint inhibitors (ICIs). Participants were aged 18 years or older with advanced unresectable, locally advanced or metastatic stage IV ccRCC, with disease progression following anti-PD-1 or anti-PD-L1 therapy with or without previous VEGFR-TKIs. Participants were randomly assigned 1:1 to receive belzutifan-lenvatinib (n=371) or cabozantinib (n=376) until disease progression or unacceptable adverse events occurred. Dual primary endpoints were progression-free survival (PFS) by masked independent central review and overall survival (OS). At the second interim analysis (median follow-up 29.0 months (IQR 23.7-34.9) median PFS was 14.8 months with belzutifan-lenvatinib versus 10.7 months with cabozantinib (HR 0.70; p<0.0001); median OS was 34.9 months versus 27.6 months (HR 0.85; p=0.061). Grade 3 or worse treatment-emergent adverse events occurred in 84% of participants in the belzutifan-lenvatinib group and 83% of participants in the cabozantinib group, most commonly hypertension in both groups. Treatment-related adverse events led to two deaths in the belzutifan-lenvatinib group and one death in the cabozantinib group. The authors conclude that belzutifan-lenvatinib represents a novel and efficacious treatment option. Althoug OS was not significantly different between the groups, beltuzifan-lenvatinib might be a new standard of care for patients with advanced ccRCC with disease progression after anti-PD-1 or anti-PD-L1 therapy.