FDA approves belzutifan plus lenvatinib for advanced clear cell renal cell carcinoma

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

“While there has been much progress in the first-line treatment of advanced kidney cancer, we have limited options to offer patients if the disease progresses after treatment with a PD-1/PD-L1 immunotherapy,” said Robert J. Motzer, MD, principal investigator of LITESPARK-011 and genitourinary medical oncologist at Memorial Sloan Kettering Cancer Center, in a news release.^2,3 “With this FDA approval of belzutifan plus lenvatinib, we have a new treatment option for patients who progress following treatment with anti-PD-1/PD-L1 therapy—an important development for patients and the physicians who care for them.”

Data on belzutifan plus lenvatinib

The approval is supported by data from the phase 3 LITESPARK-011 trial (NCT04586231), which demonstrated that the combination of belzutifan plus lenvatinib significantly improved progression-free survival (PFS) vs cabozantinib (Cabometyx) in patients with previously treated advanced ccRCC. The results were published in The Lancet.⁴

The phase 3, open-label LITESPARK-011 trial enrolled 747 patients between March 5, 2021, and September 1, 2023. Patients were eligible for enrollment if they were 18 years or older and had unresectable, locally advanced, or metastatic stage IV ccRCC. Participants also needed to have a Karnofsky Performance Status score of at least 70%, disease 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 therapy. 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 receive either 120 mg belzutifan plus 20 mg lenvatinib orally once daily or 60 mg cabozantinib 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.

Efficacy and safety data

The combination of belzutifan plus lenvatinib demonstrated a 26% reduction in the risk of disease progression or death compared with cabozantinib (HR, 0.74; 95% CI, 0.61 to 0.89; 1-sided P = .00095). The median PFS was 14.6 months (95% CI, 11.1 to 16.6) with the combination vs 10.6 months (95% CI, 9.2 to 11.1) with cabozantinib.

Related: Robert Motzer, MD, unpacks LITESPARK-011 results of belzutifan plus lenvatinib in advanced RCC

The final OS analysis did not demonstrate a statistically significant difference between the 2 arms (HR, 0.85; 95% CI, 0.70 to 1.03). The median OS was 33.7 months (95% CI, 29 to 46.9) in the combination arm vs 28.6 months (95% CI, 24.1 to 31.4) with cabozantinib.

Results from the trial’s key secondary end points showed significantly higher ORR with the combination, with a rate of 53% (95% CI, 47 to 58) in the belzutifan–lenvatinib arm vs 40% (95% CI, 35 to 45) in the cabozantinib arm (P = .0002).

Overall, the median duration of exposure to belzutifan was 15.8 months (range, 1 day to 50.6 months) and the median duration of exposure to lenvatinib was 14.5 months (range, 1 day to 50.6 months).

Serious adverse events (AEs) were reported in 54% of patients in the belzutifan–lenvatinib arm. The most common serious AEs, reported in ≥2% of patients, included hypoxia (6%), pneumonia (5%), hyponatremia (3.2%), acute kidney injury (3%), hemorrhage (2.7%), anemia (2.7%), cardiac failure (2.4%) and diarrhea (2.4%).

Overall, the authors concluded, “Although overall survival was not significantly different between the groups, these results highlight that combining drugs with different mechanisms of action can improve outcomes in a difficult-to-treat population. Belzutifan plus lenvatinib addresses an unmet clinical need and might represent a potential new standard of care in this disease setting.”

REFERENCES

1. FDA approves belzutifan in combination with lenvatinib for advanced renal cell carcinoma with a clear cell component. News release. US Food & Drug Adminstration. 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?utm_medium=email&utm_source=govdelivery

2. U.S. FDA Approves WELIREG^® (belzutifan) Plus LENVIMA^® (lenvatinib) for Certain Previously Treated Adult Patients With Advanced Renal Cell Carcinoma With a Clear Cell Component (ccRCC). News release. Eisai. September 25, 2026. Accessed September 25, 2026. https://us.eisai.com/press-releases/us-fda-approves-welireg-belzutifan-plus-lenvima-lenvatinib-for-certain-previously-treated-adult-patients-with-advanced-renal-cell-carcinoma-with-a-clear-cell-component-ccrcc

3. U.S. FDA Approves WELIREG® (belzutifan) Plus LENVIMA® (lenvatinib) for Certain Previously Treated Adult Patients With Advanced Renal Cell Carcinoma With a Clear Cell Component (ccRCC). News release. Merck. September 25, 2026. Accessed September 25, 2026. https://www.merck.com/news/u-s-fda-approves-welireg-belzutifan-plus-lenvima-lenvatinib-for-certain-previously-treated-adult-patients-with-advanced-renal-cell-carcinoma-with-a-clear-cell-component-ccrcc/

4. 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:S0140-6736(26)01089-5. doi:10.1016/S0140-6736(26)01089-5