FDA Approves Belzutifan Plus Lenvatinib for Advanced ccRCC

The FDA has approved belzutifan (Welireg) plus lenvatinib (Lenvima) for the treatment of adult patients with advanced renal cell carcinoma with a clear cell component (ccRCC) after a PD-1 or PD-L1 inhibitor.¹

This regulatory decision was backed by data from the open-label, randomized, active-controlled, LITESPARK-011 trial (NCT04586231). The belzutifan combination significantly improved progression-free survival vs cabozantinib (Cabometyx), at a median of 14.6 months (95% CI, 11.1-16.6) and 10.6 months (95% CI, 9.2-11.1), respectively (HR, 0.74; 95% CI, 0.61-0.89; 1-sided P = .00095).

Although the combination led to a numerical improvement in overall survival (OS) vs single-agent cabozantinib, the difference between the arms was not determined to be statistically significant. The median OS in the respective arms was 33.7 months (95% CI, 29.0-46.9) and 28.6 months (95% CI, 24.1-31.4), translating to a hazard ratio of 0.85 (95% CI, 0.70-1.03).

Moreover, belzutifan plus lenvatinib induced an objective response rate (ORR) of 53% (95% CI, 47%-58%), which was slightly higher than the 40% (95% CI, 35%-45%) achieved with cabozantinib (1-sided P = .0002).

What was the design of LITESPARK-011?

This trial enrolled 747 patients with locally advanced or metastatic ccRCC who had progressed on or following treatment with a PD-1 or PD-L1 inhibitor, or within 6 months of completing adjuvant therapy with a PD-1 inhibitor. Patients were required to have a Karnofsky Performance Status (KPS) score of at least 70% and to have received no more than 2 prior systemic regimens.²

Patients were randomly assigned 1:1 to receive oral belzutifan at 120 mg once daily plus oral lenvatinib at 20 mg once daily (n = 371), or oral cabozantinib at 60 mg once daily (n = 376).

Stratification factors included International Metastatic Renal Cell Carcinoma Database Consortium prognostic score (0 vs 1 to 2 vs 3 to 6), line of treatment for prior anti–PD-(L)1 (frontline, adjuvant, neoadjuvant/adjuvant vs second line), and geographic region (North America vs western Europe vs rest of world).

The dual primary end points of the study were PFS by blinded independent central review (BICR) and RECIST v1.1 criteria and OS. ORR by BICR and RECIST 1.1 served as a key secondary end point. Other secondary end points comprised duration of response (DOR) and safety. Investigators also examined time to deterioration in patient-reported outcomes.

What were the baseline characteristics of patients enrolled in LITESPARK-011?

The median patient age in the combination arm was 63.0 years (range, 30-85) vs 62.5 years (range, 30-86). Most patients were male (73.6% vs 77.7%) and had a KPS score of 90 or 100 (74.4% vs 73.7%). In terms of geographic region, 17.3% of those in the belzutifan/lenvatinib arm were from North America, 59.6% from Western Europe, and 23.2% from the rest of the world; in the cabozantinib arm, these rates were 16.8%, 57.4%, and 17.6%, respectively. Most patients across the combination and monotherapy arms had an IMDC prognostic risk that was intermediate (score 1-2), at 60.9% and 57.2%, respectively. More than half of patients had received 1 prior line of adjuvant therapy (67.9% vs 66.8%), and about half had received 1 prior VEGF TKI (54.7% vs 54.5%).

What prior data were reported from LITESPARK-011?

At a data cutoff date of April 9, 2025, the median PFS with belzutifan plus lenvatinib was 14.8 months (95% CI, 11.2-16.6) vs 10.7 months (95% CI, 9.2-11.1) with cabozantinib (HR, 0.70; 95% CI, 0.59-0.84; 1-sided P = .00007). The 12-month PFS rates in the respective arms were 55.0% and 41.0%, and the 24-month PFS rates were 35.6% vs 19.1%.

The median OS with the combination was 34.9 months (95% CI, 27.5-not reached) vs 27.6 months (95% CI, 24.0-31.4) with the monotherapy (HR, 0.85; 95% CI, 0.68-1.05; 1-sided P = .06075). In the belzutifan/lenvatinib arm, the 12- and 24-month OS rates were 79.7% and 62.8%, respectively; in the cabozantinib arm, these rates were 77.7% and 55.4%.

The ORRs in the respective arms were 52.6% (95% CI, 47.3%-57.7%) and 40.2% (95% CI, 35.2%-45.3%), translating to an estimated difference of 12.4% (95% CI, 5.3%-19.3%). The median DOR with the combination was 23.0 months (95% CI, 2.0-44.3+) vs 12.3 months (95% CI, 1.8+ to 35.9+) with the monotherapy. The 12- and 24-month DOR rates with belzutifan plus lenvatinib were 66.7% and 49.5%, respectively; these rates were 50.0% and 25.5%, respectively, with cabozantinib.

What was the safety profile of belzutifan plus lenvatinib in this population of patients with ccRCC?

Adverse effects (AEs) were reported in 99.7% of patients, with 84.1% of effects grade 3 or higher in severity. Serious AEs occurred in 51.6% of patients who received the regimen. Toxicities led to dose reductions of VEGFR TKI or belzutifan for 66.5% and 33.8% of patients, respectively. AEs led to discontinuation of all study drugs for 11.1% of patients, of belzutifan for 16.8% of patients, or of VEGFR TKI for 21.1% of patients.

Treatment-related AEs (TRAEs) occurred in 97.6% of patients who received the combination, with 71.6% of these effects grade 3 or higher. Serious TRAEs were reported in 26.5% of patients who received belzutifan plus lenvatinib. Two TRAEs proved fatal in this arm.

The most common treatment-emergent AEs reported in at least 20% of patients who received the combination included anemia (69.2%), hypertension (58.9%), diarrhea (52.7%), fatigue (45.1%), nausea (40.5%), decreased appetite (39.2%), proteinuria (36.8%), hypothyroidism (35.7%), vomiting (31.4%), arthralgia (28.9%), asthenia (28.4%), decreased weight (28.1%), constipation (26.2%), headache (22.2%), increased aspartate aminotransferase level (21.1%), palmar-plantar erythrodysesthesia syndrome (20.5%), increased alanine aminotransferase level (18.9%), stomatitis (14.1%), and dysgeusia (12.4%).

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://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-combination-lenvatinib-advanced-renal-cell-carcinoma-clear-cell-component
2. 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):LBA417. doi:10.1200/JCO.2026.44.7_suppl.LBA417