A new combination treatment for advanced kidney cancer has moved one step closer to European approval. Merck has announced that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending belzutifan plus lenvatinib for adults with advanced renal cell carcinoma with a clear cell component (ccRCC) following treatment with a PD-1 or PD-L1 inhibitor.
The recommendation follows positive findings from the Phase 3 LITESPARK-011 trial, which demonstrated improved progression-free survival (PFS) with the combination compared with cabozantinib.
If authorized, belzutifan plus lenvatinib would become the first approved combination of a hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor and a multitargeted vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) in the European Union.
The CHMP opinion is not yet a final marketing authorization. The European Commission will now review the recommendation, with a decision expected within approximately two months.
LITESPARK-011: The Phase 3 Trial Behind the Recommendation
The regulatory recommendation is supported by LITESPARK-011 (NCT04586231), a randomized, open-label Phase 3 study evaluating belzutifan plus lenvatinib against cabozantinib in patients with previously treated advanced clear cell renal cell carcinoma.
The study enrolled 747 patients, randomized into two treatment groups. A total of 371 patients received belzutifan 120 mg plus lenvatinib 20 mg orally once daily, while 376 patients received cabozantinib 60 mg orally once daily. Eligible participants had locally advanced or metastatic disease that progressed on or after PD-1 or PD-L1 inhibitor therapy, or within six months of completing adjuvant treatment with a PD-1 inhibitor.
The trial had two primary endpoints: progression-free survival, assessed by blinded independent central review, and overall survival.
Belzutifan Plus Lenvatinib Reduced the Risk of Progression or Death by 26%
The LITESPARK-011 trial demonstrated a statistically significant improvement in PFS with belzutifan plus lenvatinib compared with cabozantinib.
In the analysis supporting regulatory review, median PFS was 14.6 months with the combination versus 10.6 months with cabozantinib, corresponding to a 26% relative reduction in the hazard of disease progression or death (HR 0.74; 95% CI 0.61–0.89).
The final analysis, presented at the ESMO Congress 2026, also demonstrated sustained improvements in tumor response outcomes.
The objective response rate was 53.1% with belzutifan plus lenvatinib compared with 40.2% with cabozantinib, indicating greater tumor shrinkage with the combination.
Responses were also more durable. The median duration of response reached 22.0 months in the combination group, compared with 11.9 months in the cabozantinib group, suggesting that patients who responded to belzutifan plus lenvatinib experienced longer-lasting disease control.
Median overall survival was 33.7 months among patients receiving belzutifan plus lenvatinib, compared with 28.6 months among those treated with cabozantinib. However, the difference did not reach the trial’s prespecified threshold for statistical significance (HR 0.85; 95% CI 0.70–1.03).
This distinction is important: the combination has demonstrated a clear progression-free survival benefit, but a statistically significant overall survival advantage has not been established.
The initial trial findings were presented at the 2026 ASCO Genitourinary Cancers Symposium, with subsequent results published in The Lancet. The final prespecified analysis was also published in Annals of Oncology.
Safety Findings: Anemia, Hypoxia and Hypertension Remain Important
The combination’s safety profile was generally consistent with the known adverse effects of its individual components, although treatment-related toxicity remains an important consideration.
At the final analysis, grade 3 or higher treatment-emergent adverse events occurred in 85.4% of patients receiving belzutifan plus lenvatinib and 83.0% receiving cabozantinib.
Among patients receiving the combination, decreased hemoglobin was reported in 87%, while hypoxia occurred in 16%, including grade 3–4 hypoxia in 12%.
Serious cardiac dysfunction, including reduced left ventricular ejection fraction and heart failure, is another recognized concern with the combination. Grade 3 or higher cardiac dysfunction adverse events were reported in 6% of patients.
These findings highlight the importance of careful patient selection and monitoring of hemoglobin levels, oxygen saturation, blood pressure and cardiovascular function during treatment.
Why Combining HIF-2α and VEGFR Inhibition Matters
The combination brings together two different therapeutic approaches targeting biological pathways involved in renal cell carcinoma.
Belzutifan selectively inhibits HIF-2α, a transcription factor associated with cellular responses to reduced oxygen availability. In clear cell renal cell carcinoma, alterations in the von Hippel-Lindau (VHL) pathway can contribute to abnormal HIF-2α activity, promoting tumor growth and angiogenesis.
Lenvatinib is a multitargeted tyrosine kinase inhibitor that blocks several receptors involved in tumor angiogenesis and growth, including VEGFRs.
By inhibiting both HIF-2α signaling and receptor-mediated pathways involved in tumor blood vessel formation, the combination offers a treatment strategy with complementary mechanisms of action.
This approach is particularly relevant as clinicians seek effective treatment options for patients whose disease has progressed following immune checkpoint inhibitor therapy.
From US Approval to a Potential New European Option
The positive CHMP opinion follows the US Food and Drug Administration’s approval of belzutifan plus lenvatinib on September 24, 2026, for adults with advanced ccRCC following PD-1 or PD-L1 inhibitor treatment.
The European regulatory recommendation represents another milestone in the combination’s development and could expand treatment options for patients whose disease progresses after immunotherapy-based regimens.
Commenting on the decision, Dr. Christina Derleth, Vice President of Global Oncology Clinical Development at Merck Research Laboratories, stated:
“This positive opinion is a meaningful step toward potentially bringing this first-of-its-kind regimen to patients in need in the European Union”
The European Commission’s forthcoming decision will determine whether this combination becomes available under an expanded European indication.
For clinicians treating advanced renal cell carcinoma, the findings add another potential option to the evolving post-immunotherapy treatment landscape, while emphasizing the importance of balancing improved disease control against treatment-related toxicity.
Read further on OncoDaily: FDA Approved Belzutifan Plus Lenvatinib in Advanced ccRCC
