LITESPARK-011

LITESPARK-011 (NCT04586231; MK-6482-011) is an open-label, randomised, active-controlled phase 3 trial at 184 centres in 25 countries, sponsored by Merck Sharp & Dohme with Eisai. Adults with advanced unresectable, locally advanced or metastatic clear-cell renal cell carcinoma whose disease 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 to cabozantinib 60 mg, all taken by mouth once daily until progression or unacceptable toxicity. Randomisation was stratified by IMDC prognostic 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; the study counted as positive if either was met.

Between March 2021 and September 2023, 955 people were screened and 747 randomised (371 to belzutifan plus lenvatinib, 376 to cabozantinib). At the second interim analysis (data cutoff 9 April 2025; median follow-up 29.0 months), which was the final analysis for progression-free survival, median progression-free survival was 14.8 months (95 percent CI 11.2 to 16.6) with belzutifan plus lenvatinib against 10.7 months (9.2 to 11.1) with cabozantinib (hazard ratio 0.70, 0.59 to 0.84; one-sided p less than 0.0001). Overall survival, an interim result, was not significantly different: median 34.9 months (27.5 to not reached) against 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 often hypertension (31 and 29 percent); treatment-related adverse events led to two deaths on belzutifan plus lenvatinib and one on cabozantinib (Lancet, 12 August 2026).