Interim Efficacy Data Favor Belzutifan/Lenvatinib in Advanced RCC

At an interim analysis of the phase 3 LITESPARK-011 trial (NCT04586231), the oral combination of belzutifan (Welireg) plus lenvatinib (Lenvima) produced progression-free survival (PFS) benefits in patients with advanced renal cell carcinoma (RCC), meeting one of the study’s co-primary end points.¹

These efficacy data showed a statistically significant and clinically meaningful improvement in PFS compared with cabozantinib (Cabometyx), an orally-administrated tyrosine kinase inhibitor (TKI) approved and indicated for treatment of advanced RCC.^2,3 While the study’s other primary end point of overall survival (OS) did not reach statistical significance as of the data cutoff for this analysis, Merck and Eisai, sponsors, reported that the data thus far show a positive trend. Further, a positive trend has been reported for the study’s key secondary end point of objective response rate (ORR).

Regarding safety, the combination’s safety profile was reported to be consistent with those reported in prior studies for belzutifan and lenvatinib individually, with no new safety signals observed.

The sponsors plan to share these data at an upcoming medical meeting.

“Despite recent treatment advances, many patients with advanced RCC may still experience disease progression following treatment with a PD-1/L1 inhibitor,” said M. Catherine Pietanza, MD, vice president of Global Clinical Development at Merck Research Laboratories, in a news release.¹ “These positive results from LITESPARK-011 show the potential of this novel combination to reduce the risk of disease progression or death for patients who are in need of innovative options on or after treatment with immunotherapy.”

Belzutifan, a small molecule HIF-2α inhibitor, has demonstrated preliminary antitumor activity in heavily pretreated patients with advanced clear cell RCC.^3,4 Together with lenvatinib, a TKI that inhibits kinase activities of multiple VEGF receptors, the LITESPARK-011 study operates on a mechanistically-based hypothesis that combining belzutifan and lenvatinib will drive angiogenesis suppression and overcome resistance seen with prior VEGF-targeted therapies.

About LITESPARK-011

LITESPARK-011 is a global, randomized, open-label phase 3 trial evaluating the efficacy and safety of belzutifan plus lenvatinib in patients with advanced clear cell RCC who experienced progression after prior anti–PD-1/L1 therapy as either first- or second-line treatment.⁵ The study has co-primary end points of PFS and OS, with key secondary end points of ORR, duration of response, and safety. A total of approximately 708 patients are enrolled and randomized 1:1 to receive either 120 mg of oral belzutifan/lenvatinib once daily or 60 mg of oral cabozantinib once daily until documented disease progression.^3,4

On immediate next steps, Corina Dutcus, MD, senior vice president of Oncology Global Clinical Development Lead at Eisai, added in the news release, “We look forward to sharing these investigational findings with regulatory authorities worldwide, with the goal of bringing this treatment option to patients as soon as possible.”¹

REFERENCES:

1. Merck and Eisai announce WELIREG® (belzutifan) plus LENVIMA® (lenvatinib) met primary endpoint of progression-free survival (PFS) in certain previously Treated Patients With Advanced Renal Cell Carcinoma. News release. Merck. October 28, 2025. Accessed October 29, 2025. https://tinyurl.com/5eb3dwmx

2. Cabometyx. US FDA. Updated January 2021. Accessed October 29, 2025. https://tinyurl.com/mwknmr4h

3. LITESPARK-011: belzutifan plus lenvatinib vs cabozantinib in advanced renal cell carcinoma after anti-PD-1/PD-L1 therapy. Future Oncol. Published online 2023. doi:10.2217//fon-2022-0802

4. Choueiri TK, Bauer TM, Papadopoulos KP, et al. Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med. 2021;27(5):802-805. doi.org/10.1038/s41591-021-01324-7

5. A Study of Belzutifan (MK-6482) in Combination With Lenvatinib Versus Cabozantinib for Treatment of Renal Cell Carcinoma (MK-6482-011). ClinicalTrials.gov. Updated April 2, 2025. Accessed October 29, 2025. https://clinicaltrials.gov/study/NCT04586231