Belzutifan plus lenvatinib extends PFS vs cabozantinib in advanced renal cell carcinoma

The phase 3 LITESPARK-011 trial (NCT04586231) has met its co-primary end point of progression-free survival (PFS), Merck and Eisai reported in a joint news release.¹

At a pre-specified interim analysis, data showed that the combination of belzutifan (Welireg) plus lenvatinib (Lenvima) led to a statistically significant and clinically meaningful improvement in PFS vs cabozantinib (Cabometyx) in patients with locally advanced or metastatic clear cell renal cell carcinoma (ccRCC) whose disease progressed on or after treatment with an anti-PD-1/L1 therapy.

The combination also showed a statistically significant improvement in the trial’s key secondary end point of objective response rate (ORR). There was a trend toward improvement in the co-primary end point of overall survival (OS), although the difference did not reach statistical significance at the time of the interim analysis.

According to Merck and Eisai, “LITESPARK-011 marks the first positive phase 3 study of a HIF-2 alpha inhibitor in combination with a multi-targeted VEGF tyrosine kinase inhibitor.”

“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, global clinical development, Merck Research Laboratories, in the 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.”

No new safety signals were observed at the time of the interim analysis; the safety profile for the combination was consistent with the known profiles for each individual agent. Merck and Eisai plan to share data from LITESPARK-011 at an upcoming medical meeting and with regulatory authorities worldwide.

“We are encouraged by the data observed in the LITESPARK-011 trial, which bolster our belief in the role of LENVIMA in various combinations as a treatment option for patients impacted by advanced RCC,” said Corina Dutcus, MD, senior vice president, oncology global clinical development lead at Eisai, in the news release.¹ “These results further demonstrate Eisai’s commitment to people living with advanced RCC and invigorate our mission to address the unmet needs of patients with difficult-to-treat cancers. 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. We extend our heartfelt gratitude to the patients, caregivers and investigators for their participation in this study, and for helping us move this important research forward.”

In total, the open-label, phase 3 LITESPARK-011 trial enrolled an estimated 708 adult patients with advanced RCC with a clear cell component. Participants were eligible for enrollment if they had experienced disease progression on or after an anti-PD-1/L1 therapy, had a Karnofsky performance status score of at least 70%, and had adequate organ function.²

Those enrolled in the study were randomly assigned to receive belzutifan 120 mg orally once daily plus lenvatinib 20 mg orally once daily or to cabozantinib 60 mg orally once daily. The trial’s dual primary end points are PFS per RECIST v1.1 by blinded independent central review and OS. Key secondary end points include ORR, duration of response, and safety.

Primary completion of the trial is expected in February 2026, with final completion slated for February 2027.

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 2025. https://www.businesswire.com/news/home/20251028392813/en/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

2. A study of belzutifan (MK-6482) in combination with lenvatinib versus cabozantinib for treatment of renal cell carcinoma (MK-6482-011). ClinicalTrials.gov. Last updated April 2, 2025. Accessed October 28, 2025. https://clinicaltrials.gov/study/NCT04586231