FDA Approves Belzutifan Plus Lenvatinib for Advanced Renal Cell Carcinoma After Immunotherapy

The FDA has approved belzutifan (Welireg; Merck & Co) in combination with lenvatinib (Lenvima; Eisai Inc) for adults with advanced renal cell carcinoma (RCC) with a clear cell component (ccRCC) following a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor. The decision arrives ahead of the October 4, 2026, target action date the agency set when it accepted the supplemental new drug applications earlier this year.^1,2

What Is Belzutifan Plus Lenvatinib?

Belzutifan is a first-in-class oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor. It reduces transcription of HIF-2α target genes associated with cellular proliferation, angiogenesis, and tumor growth. Lenvatinib is an oral multiple receptor tyrosine kinase inhibitor (TKI) that inhibits vascular endothelial growth factor (VEGF) receptors 1 through 3, as well as FGFR1-4, PDGFRα, KIT, and RET.²

The recommended dosage is lenvatinib 20 mg plus belzutifan 120 mg, both taken orally once daily until disease progression or unacceptable toxicity.¹

The approval broadens belzutifan's role in RCC. The agent was already indicated as monotherapy for advanced ccRCC following a PD-1/PD-L1 inhibitor and a VEGF-TKI. In June 2026, the FDA also approved belzutifan with pembrolizumab (Keytruda; Merck & Co.) for the adjuvant treatment of adults with RCC with a clear cell component.^2,3

LITESPARK-011 Trial Results

Efficacy was evaluated in the open-label, randomized, active-controlled phase 3 LITESPARK-011 trial (NCT04586231). The trial enrolled 747 patients with locally advanced or metastatic ccRCC that had progressed on or after a PD-1 or PD-L1 inhibitor or within 6 months of completing adjuvant PD-1 inhibitor therapy. Patients were randomly assigned 1:1 to receive belzutifan plus lenvatinib or cabozantinib.¹

The combination demonstrated a statistically significant improvement in progression-free survival (PFS) by blinded independent central review. Median PFS was 14.6 months with the combination vs 10.6 months with cabozantinib (HR, 0.74; 95% CI, 0.61-0.89; 1-sided P = .00095). The objective response rate was 53% vs 40%, respectively. However, the final overall survival (OS) analysis was not statistically significant, with a median OS of 33.7 months vs 28.6 months (HR, 0.85; 95% CI, 0.70-1.03).¹

At the 2026 ASCO Genitourinary Cancers Symposium, investigators also reported a median duration of response of 23.0 months with the combination vs 12.3 months with cabozantinib.²

Yousef Zakharia, MD, chair of the genitourinary malignancy program at the Mayo Clinic enterprise, highlighted the durability data. He noted that 49% of patients receiving the combination were still responding at 2 years, compared with 25% of those receiving cabozantinib, and predicted the combination would become a "practice-changing regimen."⁴

Clinical Implications for Pharmacists

Because belzutifan plus lenvatinib is an all-oral regimen, pharmacists are central to adherence support, toxicity monitoring, and drug interaction screening. Coadministration of belzutifan with UGT2B17 or CYP2C19 inhibitors increases belzutifan exposure. Belzutifan also lowers concentrations of CYP3A4 substrates, so sensitive CYP3A4 substrates should be avoided when possible.²

Belzutifan may render some hormonal contraceptives ineffective. Patients of reproductive potential should therefore use effective nonhormonal contraception during treatment and for 1 week after the last dose. For lenvatinib, blood pressure should be controlled before initiation. It should then be monitored after 1 week, every 2 weeks for the first 2 months, and at least monthly thereafter.²

In LITESPARK-011, grade 3 or higher treatment-related adverse events occurred in 71.6% of patients receiving the combination vs 65.8% of those receiving cabozantinib. Discontinuation rates due to adverse events were similar between the 2 groups (11.1% vs 11.3%).²

Warnings and Precautions

Belzutifan carries a boxed warning for embryo-fetal toxicity, along with warnings and precautions for anemia and hypoxia. Labeling for the combination also includes cardiac dysfunction. Hemoglobin and oxygen saturation should be monitored before and periodically throughout treatment.^1,2

Lenvatinib warnings and precautions include hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal impairment, proteinuria, diarrhea, fistula formation and gastrointestinal perforation, QT prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, thyroid dysfunction, impaired wound healing, osteonecrosis of the jaw, and embryo-fetal toxicity.¹

REFERENCES

1. FDA approves belzutifan in combination with lenvatinib for advanced renal cell carcinoma with a clear cell component. News release. FDA. September 24, 2026. Accessed September 24, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-combination-lenvatinib-advanced-renal-cell-carcinoma-clear-cell-component

2. WELIREG (belzutifan) plus LENVIMA (lenvatinib) reduced the risk of disease progression or death by 30% compared to cabozantinib in certain previously treated patients with advanced renal cell carcinoma (RCC). News release. Merck. February 28, 2026. Accessed September 24, 2026. https://www.merck.com/news/welireg-belzutifan-plus-lenvima-lenvatinib-reduced-the-risk-of-disease-progression-or-death-by-30-compared-to-cabozantinib-in-certain-previously-treated-patients-with-advanced-renal-ce/

3. FDA approves belzutifan with pembrolizumab for adjuvant treatment of renal cell carcinoma. News release. FDA. June 12, 2026. Accessed September 24, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-pembrolizumab-adjuvant-treatment-renal-cell-carcinoma

4. Zakharia Y. LITESPARK-011 signals shifting paradigm in RCC. Targeted Oncology. March 16, 2026. Accessed September 24, 2026. https://www.targetedonc.com/view/new-combinations-reshape-treatment-landscape-in-renal-cell-carcinoma