New results from the KEYMAKER-U03 substudy 03A (2026) show that several three-drug immunotherapy combinations work well as first-line treatment for advanced clear cell renal cell carcinoma (ccRCC).
The study compared the current standard treatment—pembrolizumab plus lenvatinib—with four new triplet regimens. The standard therapy had an overall response rate (ORR) of 80.6%. Adding belzutifan resulted in a similar ORR of 77.5%. The combination of quavonlimab with pembrolizumab and lenvatinib achieved a 71.3% response rate. Other combinations showed lower response rates.
The belzutifan triplet also showed strong disease control, with a median progression-free survival of 31.8 months compared with 26.3 months for the standard two-drug regimen. Median overall survival has not yet been reached in any group, meaning most patients are still alive. Side effects were generally similar to the known safety profiles of the individual drugs, and the belzutifan combination was especially well tolerated, with no dose-limiting toxicities reported.
Overall, the study suggests that adding a third drug to the standard pembrolizumab and lenvatinib combination is possible and may improve long-term outcomes. A larger phase 3 trial, LITESPARK-012, is now underway to determine whether these triplet therapies will become the new standard of care.