Abstract
PARTICIPANTS AND METHODS
Adult participants with advanced ccRCC that progressed on or after anti-PD-(L)1 therapy were randomly assigned (1:1) to 120 mg belzutifan plus 20 mg lenvatinib or 60 mg cabozantinib orally once daily until disease progression or unacceptable adverse events. Dual primary endpoints were PFS by blinded independent central review (BICR) and OS. ORR by BICR was a key secondary endpoint; safety and duration of response (DOR) by BICR were secondary endpoints.
CONCLUSIONS
Belzutifan plus lenvatinib continued to demonstrate PFS, ORR, and DOR benefit versus cabozantinib with additional follow-up; OS favored the combination but did not reach statistical significance at final analysis. Safety profile of belzutifan plus lenvatinib remained consistent with each drug as monotherapy. These findings continue to support belzutifan plus lenvatinib as a treatment option in advanced ccRCC following anti-PD-(L)1 therapy.
RESULTS
At final analysis, median time from randomization to data cutoff date (2 February 2026) was 38.8 months (range, 29.1-59.0). 371 participants were assigned to belzutifan plus lenvatinib and 376 to cabozantinib. Belzutifan plus lenvatinib continued to demonstrate benefit versus cabozantinib in PFS (HR 0.74, 95% CI 0.62-0.88), ORR (53.1% vs 40.2%), and DOR (22.0 vs 11.9 months). Mature OS results did not reach statistical significance at final analysis (median 33.7 versus 28.6 months; HR 0.85, 95% CI 0.70-1.03; one-sided P=0.04689 [prespecified boundary 0.0223]). Grade ≥3 treatment-emergent adverse events occurred in 85.4% of the belzutifan plus lenvatinib group versus 83.0% of the cabozantinib group.
BACKGROUND
The phase 3, randomized, open-label LITESPARK-011 trial (NCT04586231) investigated belzutifan plus lenvatinib versus cabozantinib in participants with advanced clear-cell renal-cell carcinoma (ccRCC) following anti-PD-(L)1 therapy. At earlier analyses, belzutifan plus lenvatinib significantly improved progression-free survival (PFS) and objective response rate (ORR) versus cabozantinib. Overall survival (OS) was tested but did not reach significance. We present the final analysis of LITESPARK-011.