FDA accepts sNDA for belzutifan plus lenvatinib for advanced renal cell carcinoma

The FDA has accepted supplemental new drug applications (sNDAs) seeking approval of belzutifan (Welireg) plus lenvatinib (Lenvima) for the treatment of adult patients with advanced clear cell renal cell carcinoma (ccRCC) following previous treatment with a PD-1 or PD-L1 inhibitor.¹

The agency has set a Prescription Drug User Fee Act (PDUFA), or target action date, of October 4, 2026.

The applications are supported by data from the LITESPARK-011 trial (NCT04586231), which were presented by Robert J. Motzer, MD, at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California.² Overall, the trial demonstrated that the combination of belzutifan plus lenvatinib improved progression-free survival (PFS) and objective response rate (ORR) compared with cabozantinib (Cabometyx) in patients with previously treated ccRCC.

“Choosing the right treatment for patients with advanced renal cell carcinoma after immunotherapy has been an ongoing challenge, and treatment options in this setting had not previously been evaluated against a current standard of care tyrosine kinase inhibitor in a phase 3 trial,” explained Motzer, a genitourinary medical oncologist at Memorial Sloan Kettering Cancer Center, in a news release from Merck.¹ “The LITESPARK-011 study demonstrated a 30% reduction in the risk of disease progression or death with belzutifan plus lenvatinib compared to cabozantinib, and 52.6% of patients experienced a response to treatment. These findings mark a critical step forward for these patients.”

The phase 3, open-label LITESPARK-011 trial enrolled a total of 747 patients between March 5, 2021, and September 1, 2023. Patients were eligible for enrollment if they had unresectable, locally advanced, or metastatic ccRCC who had a Karnofsky Performance Status score of at least 70%, had progression on or after anti-PD-(L)1 monoclonal antibody as first- or second-line therapy or progression 6 months or sooner after the last dose adjuvant anti-PD-(L)1 monoclonal antibody. Patients were still eligible for inclusion if they had received prior treatment with a VEGFR-TKI.

Participants in the study were randomly assigned 1:1 to either belzutifan/lenvatinib 120 mg orally once daily plus lenvatinib 20 mg orally once daily or cabozantinib 60 mg orally once daily. The dual primary end points were PFS per RECIST 1.1 by blinded independent central review (BICR) and overall survival (OS). The key secondary end point was objective response rate (ORR) per RECIST 1.1 by BICR. Other secondary end points included duration of response (DOR) per RECIST 1.1 by BICR and safety. Time to deterioration in patient-reported outcomes was an exploratory end point.

At a median follow-up of 29 months (range, 19.3 to 49.2), the combination of belzutifan plus Lenvatinib demonstrated a 30% reduction in the risk of disease progression or death compared with cabozantinib (HR,0.70; 95% CI, 0.59 to 0.84; P = .00007). The median PFS was 14.8 months (95% CI, 11.2 to 16.6) with the combination vs 10.7 months (95% CI, 9.2 to 11.1) with cabozantinib.

The data also showed a trend toward improvement in overall survival (OS) with the belzutifan/lenvatinib combination vs cabozantinib (HR, 0.85; 95% CI, 0.68 to 1.05; P = .06075). The median OS was 34.9 months arm (95% CI, 27.5 to not reached) in the combination vs 27.6 months (95% CI, 24 to 31.4) with cabozantinib. OS will continue to be evaluated per the trial protocol.

Data from the trial’s 2 key secondary end points were also shared with a median follow-up of 19.6 months (range, 9.9 to 39.8). Results showed a statistically significant improvement in ORR with the combination, with a rate of 52.6% (95% CI, 47.3 to 57.7) in the belzutifan/Lenvatinib arm vs 39.6% (95% CI, 34.6 to 44.8) in the cabozantinib arm. At a second interim analysis with a median follow-up of 29 months, the median duration of response was 23 months (95% CI, 2.0 to 44.3+) for the combination vs 12.3 months (95% CI, 1.8+ to 35.9+) for cabozantinib.

The median duration of therapy was 16.8 months (range, 0.03-46.9 months) for patients receiving belzutifan/lenvatinib compared with 13.2 months (range, 0.4-41.9 months) in the cabozantinib arm. Nearly all patients in each arm had a treatment-emergent adverse event (AE); specifically, 99.7% of the belzutifan/lenvatinib arm and 99.5% of the cabozantinib arm. Grade 3 treatment-related AEs were reported in 71.6% of patient in the combination arm and 65.8% of patients in the cabozantinib arm.

The rate of treatment-emergent AEs resulting in discontinuation of all study drugs was 11.1% in the belzutifan/lenvatinib arm and 11.3% in the cabozantinib arm. Two treatment-related AEs led to death in the belzutifan/lenvatinib arm, and 1 AE led to death in the cabozantinib arm.

REFERENCES

1. WELIREG® (belzutifan) Plus LENVIMA® (lenvatinib) Reduced the Risk of Disease Progression or Death by 30% Compared to Cabozantinib in Certain Previously Treated Patients With Advanced Renal Cell Carcinoma (RCC). News release. Merck. February 28, 2026. Accessed March 2, 2026. https://www.merck.com/news/welireg-belzutifan-plus-lenvima-lenvatinib-reduced-the-risk-of-disease-progression-or-death-by-30-compared-to-cabozantinib-in-certain-previously-treated-patients-with-advanced-renal-ce/

2. Motzer RJ, Park SH, McDermott RS, et al. Belzutifan (bel) plus lenvantinib (lenva) versus cabozantinib (cabo) for advanced renal cell carcinoma after anti-PD-(L)1 therapy: Open-label phase 3 LITESPARK-011 study. Presented at: 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium. February 26-28, 2026. San Francisco, California. Abstract LBA417. https://meetings.asco.org/meetings/2026-asco-genitourinary-cancers-symposium/334/16925?presentation=256659