Belzutifan plus lenvatinib versus cabozantinib in patients with previously treated advanced renal cell carcinoma (LITESPARK-011): an open-label, randomised, controlled, phase 3 trial

Primary publication of LITESPARK-011 (NCT04586231), an open-label, randomised, active-controlled phase 3 trial at 184 centres in 25 countries. Adults with advanced clear-cell renal cell carcinoma that had progressed after anti-PD-1 or anti-PD-L1 therapy, with or without a prior VEGFR tyrosine kinase inhibitor, were randomly assigned 1:1 to belzutifan 120 mg plus lenvatinib 20 mg or cabozantinib 60 mg, orally once daily, stratified by IMDC score, line of previous immunotherapy and region. The dual primary endpoints were progression-free survival by masked independent central review and overall survival in all randomised participants.

Between 5 March 2021 and 1 September 2023, 955 people were screened and 747 randomised (371 belzutifan plus lenvatinib, 376 cabozantinib); 76 percent were male and 87 percent White. At the second interim analysis (data cutoff 9 April 2025; median follow-up 29.0 months, IQR 23.7 to 34.9), progression-free survival was significantly longer with belzutifan plus lenvatinib (median 14.8 months, 95 percent CI 11.2 to 16.6, versus 10.7 months, 9.2 to 11.1; hazard ratio 0.70, 0.59 to 0.84; one-sided p less than 0.0001). Overall survival was not significantly different (median 34.9 months, 27.5 to not reached, versus 27.6 months, 24.0 to 31.4; hazard ratio 0.85, 0.68 to 1.05; one-sided p 0.061). Grade 3 or worse treatment-emergent adverse events occurred in 311 of 370 (84 percent) and 307 of 371 (83 percent) treated participants, most commonly hypertension (31 and 29 percent); treatment-related adverse events led to two deaths and one death respectively. The authors conclude that belzutifan plus lenvatinib is a novel and efficacious option that might become a new standard of care after immunotherapy, with a safety profile consistent with the individual drugs.