CHMP Recommends Approval of Belzutifan Plus Lenvatinib for Advanced ccRCC After PD-(L)1 Inhibition

The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending the approval of belzutifan (Welireg) in combination with lenvatinib (Lenvima) for the treatment of adult patients with advanced renal cell carcinoma with a clear cell component (ccRCC) following a PD-1 or PD-L1 inhibitor.¹

The European Commission (EC) will now review the recommendation for marketing authorization in the European Union, Iceland, Liechtenstein, and Norway, with a final decision expected within the next 2 months.

The CHMP opinion was based on findings from the randomized, open-label, phase 3 LITESPARK-011 trial (NCT04586231), in which belzutifan plus lenvatinib significantly improved progression-free survival (PFS) vs cabozantinib (Cabometyx). At the first interim analysis, the median PFS was 14.6 months (95% CI, 11.1-16.6) with the combination (n = 371) vs 10.6 months (95% CI, 9.2-11.1) with cabozantinib (n = 376; HR, 0.74; 95% CI, 0.61-0.89; 1-sided P = .00095).² The PFS benefit was maintained at the second interim analysis (HR, 0.70; 95% CI, 0.59-0.84; P = .00007).

At the final analysis, overall survival (OS), the other dual primary end point, did not reach statistical significance (HR, 0.85; 95% CI, 0.70-1.03).¹ The combination continued to produce a higher objective response rate (ORR) at the final analysis, at 53.1% vs 40.2% with cabozantinib, and a longer median duration of response (DOR), at 22.0 months vs 11.9 months, respectively.¹

"Patients with advanced RCC in the European Union have limited treatment options if their disease progresses following anti-PD-1 or anti-PD-L1 therapy," Christina Derleth, MD, vice president of global oncology clinical development at Merck Research Laboratories, stated in a news release. "This positive opinion is a meaningful step toward potentially bringing this first-of-its-kind regimen to patients in need in the European Union and underscores the important role of [belzutifan] plus lenvatinib as a new option in the treatment of renal cell carcinoma."

In September 2026, the FDA approved belzutifan plus lenvatinib for adult patients with advanced ccRCC following a PD-1 or PD-L1 inhibitor, with this decision also based on LITESPARK-011 data.³

How was the LITESPARK-011 trial designed?

LITESPARK-011 enrolled patients with unresectable, locally advanced or metastatic ccRCC who had a Karnofsky performance status of at least 70%, had received no more than 2 prior systemic regimens, and had experienced disease progression on or after an anti-PD-1/PD-L1 monoclonal antibody given as first- or second-line therapy, or within 6 months of the last dose of adjuvant anti-PD-1/PD-L1 therapy.² Prior VEGFR TKI therapy was permitted.

Between March 5, 2021, and September 1, 2023, a total of 747 patients at 184 sites were randomly assigned 1:1 to receive belzutifan at 120 mg orally once daily plus lenvatinib at 20 mg orally once daily or cabozantinib at 60 mg orally once daily. Randomization was stratified by International Metastatic RCC Database Consortium (IMDC) prognostic score (0 vs 1-2 vs 3-6), line of prior anti-PD-1/PD-L1 therapy (first line vs adjuvant vs perioperative vs second line), and geographic region (North America vs Western Europe vs rest of world).

The dual primary end points were PFS per RECIST 1.1 crtieria by blinded independent central review and OS; the trial was considered positive if either was met. ORR was the key secondary end point, and other secondary end points included DOR and safety. Time to deterioration in patient-reported outcomes was an exploratory end point.

What is the safety profile of belzutifan plus lenvatinib?

In the as-treated population, the median duration of therapy was 16.8 months with belzutifan plus lenvatinib (n = 370) vs 13.2 months with cabozantinib (n = 371). Grade 3 or higher treatment-emergent adverse effects (TEAEs) occurred in 84.1% vs 82.7% of patients, respectively, and serious TEAEs occurred in 51.6% vs 43.9%. Treatment-related (TRAEs) of grade 3 or higher occurred in 71.6% vs 65.8% of patients. TEAEs led to discontinuation of all study drugs in 11.1% vs 11.3% of patients.

TRAEs led to death in 2 patients (0.5%) in the combination arm, due to thrombotic microangiopathy and pneumonitis, and in 1 patient (0.3%) in the cabozantinib arm, due to hemoptysis.

The most common TEAEs with belzutifan plus lenvatinib vs cabozantinib included anemia (69.2% vs 25.6%), hypertension (58.9% vs 56.6%), diarrhea (52.7% vs 70.1%), and fatigue (45.1% vs 40.7%). Hypoxia occurred in 15.4% vs 0% of patients (grade ≥3, 11.9% vs 0%), and cardiac dysfunction occurred in 7.0% vs 1.1% (grade ≥3, 4.6% vs 0.5%).

References

1. Merck receives positive EU CHMP opinion for Welireg (belzutifan) in combination with lenvatinib for adults with advanced renal cell carcinoma with a clear cell component (ccRCC) following treatment with an anti-PD-1/PD-L1 therapy. News release. Merck. November 13, 2026. Accessed November 13, 2026. https://www.businesswire.com/news/home/20261112893799/en/Merck-Receives-Positive-EU-CHMP-Opinion-for-WELIREG-belzutifan-in-Combination-With-Lenvatinib-for-Adults-With-Advanced-Renal-Cell-Carcinoma-With-a-Clear-Cell-Component-ccRCC-Following-Treatment-With-an-Anti-PD-1PD-L1-Therapy
2. Motzer RJ, Park SH, McDermott RS, et al. Belzutifan plus lenvatinib versus cabozantinib for advanced renal cell carcinoma after anti–PD-(L)1 therapy: open-label phase 3 LITESPARK-011 study. J Clin Oncol. 2026;44(suppl 7):LBA417. doi:10.1200/JCO.2026.44.7_suppl.LBA417
3. FDA approves belzutifan in combination with lenvatinib for advanced renal cell carcinoma with a clear cell component. FDA. September 24, 2026. Accessed November 13, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-combination-lenvatinib-advanced-renal-cell-carcinoma-clear-cell-component