FDA Approves Belzutifan Plus Lenvatinib for Advanced ccRCC

The FDA granted approval for belzutifan (Welireg) in combination with lenvatinib (Lenvima) for adults with advanced renal cell carcinoma with a clear cell component (ccRCC) following progression on a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor.¹

The recommended dosage supporting the FDA approval is lenvatinib 20 mg in combination with belzutifan 120 mg once daily until disease progression or unacceptable toxicity.

The approval was based on findings from the phase 3 LITESPARK-011 trial (NCT04586231), an open-label, randomized, active-controlled study in 747 patients with advanced ccRCC. In the trial's final analysis, median progression-free survival (PFS) by blinded independent central review per RECIST v1.1 was 14.6 months (95% CI, 11.1-16.6) with belzutifan plus lenvatinib compared with 10.6 months (95% CI, 9.2-11.1) with cabozantinib (Cabometyx) (HR, 0.74; 95% CI, 0.61-0.89; 1-sided P =.00095).

Trial Design and Conduct

LITESPARK-011 was conducted at 184 medical centers across 25 countries in Asia, Australia, Europe, North America, and South America.² Of 955 individuals screened between March 5, 2021, and September 1, 2023, 747 were randomly assigned 1:1 to belzutifan plus lenvatinib (n = 371) or 60 mg cabozantinib (n = 376). Eligible participants were 18 years of age or older with advanced unresectable, locally advanced, or metastatic stage IV ccRCC that had progressed following anti–PD-1 or anti–PD-L1 therapy, with or without prior VEGFR tyrosine kinase inhibitor treatment.

Patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium prognostic score, line of prior immunotherapy, and geographic region. Of the randomized population, 565 participants (76%) were male and 182 (24%) were female; 651 (87%) were White. The dual primary end points were PFS by masked independent central review and OS, assessed in all randomized participants; safety was assessed in all randomized participants who received at least 1 dose of study treatment.

The final analysis of overall survival (OS) was not statistically significant, with a median OS of 33.7 months (95% CI, 29.0-46.9) with belzutifan plus lenvatinib vs 28.6 months (95% CI, 24.1-31.4) with cabozantinib (HR, 0.85; 95% CI, 0.70-1.03). In addition, the objective response rate (ORR) was 53% (95% CI, 47-58) with the combination vs 40% (95% CI, 35-45) with cabozantinib (1-sided P =.0002).

Published LITESPARK-011 Results

Findings from a second interim analysis published in The Lancet reported on a data cutoff of April 9, 2025 and a median follow-up of 29.0 months (interquartile range, 23.7-34.9). In that analysis, median PFS was 14.8 months (95% CI, 11.2-16.6) with belzutifan plus lenvatinib vs 10.7 months (95% CI, 9.2-11.1) with cabozantinib (HR, 0.70; 95% CI, 0.59-0.84; 1-sided P <.0001), and ORR was 52.6% (95% CI, 47.3-57.7) vs 40.2% (95% CI, 35.2-45.3), including 20 complete responses with the combination compared with 4 with cabozantinib.^2,3

Median OS at that interim analysis was 34.9 months (95% CI, 27.5-not reached) with belzutifan plus lenvatinib vs 27.6 months (95% CI, 24.0-31.4) with cabozantinib (HR, 0.85; 95% CI, 0.68-1.05; 1-sided P =.061), a difference the study authors reported as not statistically significant. Duration of response also favored the combination in that analysis, with a 24-month rate of 49.5% vs 25.5% and a median duration of response of 23.0 months vs 12.3 months for belzutifan plus lenvatinib and cabozantinib, respectively.

Safety Findings

At the second interim analysis, grade 3 or higher treatment-emergent adverse events occurred in 311 of 370 participants (84%) in the belzutifan plus lenvatinib group and 307 of 371 participants (83%) in the cabozantinib group, most commonly hypertension in both groups (114 participants [31%] with the combination and 107 [29%] with cabozantinib). Treatment-related adverse events led to 2 deaths in the belzutifan plus lenvatinib group and 1 death in the cabozantinib group. Patients remained on the combination for a longer median duration than on cabozantinib (16.8 vs 13.2 months) at that interim analysis, and the most common treatment-emergent adverse events with the combination were anemia (69.2%), hypertension (58.8%), and diarrhea (52.7%), compared with diarrhea (70.1%), hypertension (56.6%), and skin toxicity (51.2%) with cabozantinib.

Approval Background of Belzutifan

In June 2026, the FDA approved belzutifan in combination with pembrolizumab (Keytruda) as adjuvant ccRCC therapy for those at intermediate-high or high risk of recurrence based on the phase 3 LITESPARK-022 trial (NCT05239728). Belzutifan was previously approved after prior PD-1/PD-L1 therapy and VEGF TKI therapy in ccRCC based on the phase 3 LITESPARK-005 study, and also received approval in advanced pheochromocytoma and paraganglioma.

REFERENCES

1. FDA approves belzutifan in combination with lenvatinib for advanced renal cell carcinoma with a clear cell component. FDA. September 24, 2026. Accessed September 24, 2026. https://tinyurl.com/mckvxff

2. Motzer RJ, McDermott R, Park SH, et al. Belzutifan plus lenvatinib versus cabozantinib in patients with previously treated advanced renal cell carcinoma (LITESPARK-011): an open-label, randomised, controlled, phase 3 trial. Lancet. 2026;408(10557):P808-820. doi:10.1016/S0140-6736(26)01089-5

3. Motzer RJ, Park SH, McDermott RS, et al. Belzutifan (bel) plus lenvatinib (lenva) versus cabozantinib (cabo) for advanced renal cell carcinoma (RCC) after anti-PD-(L)1 therapy: open-label phase 3 LITESPARK-011 study. J Clin Oncol. 2026;44(suppl 7):417. doi:10.1200/JCO.2026.44.7_supplLBA417