Belzutifan-Based Combinations Meet DFS, PFS End Points in Renal Cell Carcinoma

October 28, 2025

Two belzutifan-based combinations met their respective primary efficacy end points of DFS and PFS in the phase 3 LITESPARK-022 and LITESPARK-011 trials.

The phase 3 LITESPARK-011 (NCT04586231) and LITESPARK-022 (NCT05239728) trials met their respective primary end points of progression-free survival (PFS) and disease-free survival (DFS) across different stages of renal cell carcinoma (RCC) with belzutifan (Welireg) in combination with either lenvatinib (Lenvima) or pembrolizumab (Keytruda), respectively, according to positive topline results.1,2

LITESPARK-011 investigated the dual oral regimen of belzutifan plus lenvatinib in patients with advanced RCC whose disease had progressed on or after prior anti-PD-1/L1 therapy.1 At a pre-specified interim analysis, a statistically significant and clinically meaningful improvement in PFS was seen with the combination vs cabozantinib (Cabometyx). The combination also showed statistically significant improvement in objective response rate (ORR). Although a trend toward improved overall survival (OS)—the study’s dual primary end point—was observed, statistical significance was not achieved at the interim analysis. Accordingly, this end point will be assessed in a subsequent analysis.

LITESPARK-022 evaluated the combination of belzutifan plus pembrolizumab in the adjuvant setting for patients with clear cell RCC following nephrectomy.2 Results demonstrated a statistically significant and clinically meaningful improvement in DFS with the regimen when compared with the control arm of pembrolizumab plus placebo. Evaluation of OS is ongoing.

Overall, the safety profiles of both combinations were consistent with those observed in previously reported studies for each individual therapy.1,2

Merck, one of the drug’s developers, noted in a news release these results position belzutifan plus lenvatinib as the first treatment regimen to show a statistically significant improvement in PFS vs cabozantinib (Cabometyx) for patients progressing after anti-PD-1/L1 therapy in a phase 3 study, and LITESPARK-011 as the first positive phase 3 study combining a hypoxia-inducible factor-2 alpha inhibitor with a multi-targeted VEGF TKI.1

“Despite recent treatment advances, many patients with advanced RCC may still experience disease progression following treatment with a PD-1/L1 inhibitor,” M. Catherine Pietanza, MD, vice president of Global Clinical Development at Merck Research Laboratories, stated the a news release. “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.”

Furthermore, LITESPARK-022 features the first combination regimen to demonstrate improvement in DFS vs pembrolizumab monotherapy in this specific patient population and is the second phase 3 study to report positive results for belzutifan as part of a combination regimen in RCC, the company added.2

“[Pembrolizumab] monotherapy given in the adjuvant setting remains an important treatment choice for patients with RCC at an increased risk of recurrence following surgery and is the only approved option to have significantly improved DFS and OS in this disease setting. Still, many of these patients do remain at risk of recurrence and continue to represent an unmet need," Pietanza noted in another press release. “These encouraging results… from LITESPARK-022 demonstrate the potential to provide additional treatment options for those most in need.”

These datasets will be shared with regulatory authorities globally and presented at upcoming medical meetings.1,2

Belzutifan-Based Combinations Meet DFS, PFS End Points in RCC: Key Takeaways

The LITESPARK-022 trial met its primary DFS end point with adjuvant belzutifan plus pembrolizumab in clear cell RCC following nephrectomy.
The LITESPARK-011 trial met its primary PFS end point with the dual oral regimen of belzutifan plus lenvatinib in PD-L1–pretreated patients with advanced RCC.
These results mark belzutifan plus lenvatinib as the first treatment regimen to signfiicantly improved PFS vs cabozantinib following anti-PD-1/L1 therapy in RCC, and belzutifan plus lenvatinib as the first combination regimen to improved DFS vs pembrolizumab alone in the adjuvant setting.

How were the LITESPARK trials designed?

LITESPARK-011 was a randomized, open-label trial enrolling an estimated 708 patients with advanced clear cell RCC who progressed on or after anti-PD-1/L1 therapy.1 Patients were randomly assigned to receive either belzutifan at 120 mg orally once daily plus lenvatinib at 20 mg orally once daily or cabozantinib at 60 mg orally once daily. The trial’s dual primary end points were PFS and OS per blinded independent central review.

LITESPARK-022 was a multicenter, randomized, double-blind study involving 1,841 patients with clear cell RCC after nephrectomy.2 Patients were randomly assigned to receive either belzutifan at 120 mg orally once daily for approximately 1 year alongside 400 mg of pembrolizumab intravenously every 6 weeks for approximately 1 year; or pembrolizumab plus oral placebo. The study’s primary end point was DFS, and OS was the key secondary end point.

What are belzutifan’s current indications and ongoing investigations?

Belzutifan is currently approved in multiple countries, including the United States, Japan and the European Union, for the treatment of adult patients with advanced clear cell RCC following treatment with a PD-1/PD-L1 inhibitor and 1 to 2 VEGF TKIs.1 Belzutifan is also approved for certain von Hippel-Lindau disease-associated neoplasms and pheochromocytoma/ paraganglioma.

Both lenvatinib and pembrolizumab display clear mechanistic rationales for serving as combination partners for belzutifan. Lenvatinib is an orally available multiple-receptor TKI that inhibits VEGFR1-3, FGFR1-4, PDGFRα, KIT, and RET, which are implicated in angiogenesis and tumor growth. Pembrolizumab is an anti-PD-1 therapy that works by blocking the PD-1/PD-L1 pathway to enhance immune response.

The potential of combining these mechanisms is further highlighted by findings from substudy 3A of the umbrella phase 1/2 KEYMAKER-U03 trial (NCT04626479), findings from which were presented at the 2025 ESMO Congress and showed improved efficacy outcomes with the belzutifan triplet vs multiple other pembrolizumab-based triplets in advanced clear cell RCC.3

This triplet is currently under evaluation in the phase 3 LITESPARK-012 study (NCT047367706).1

References

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 28, 2025. https://www.merck.com/news/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-c/
Merck announces WELIREG (belzutifan) plus KEYTRUDA (pembrolizumab) met primary endpoint of disease-free survival (DFS) in certain patients with clear cell renal cell carcinoma following nephrectomy. News release. Merck. October 28, 2025. Accessed October 28, 2025. https://www.merck.com/news/merck-announces-keytruda-pembrolizumab-plus-welireg-belzutifan-met-primary-endpoint-of-disease-free-survival-dfs-in-certain-patients-with-clear-cell-renal-cell-carcinoma-rcc-follow/
Suarez Rodriguez C, Rojas CI, Shin SJ, et al. First-line pembrolizumab-based regimens for advanced clear cell renal cell carcinoma: KEYMAKER-U03 substudy 03A. Presented at: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. Abstract LBA96.