FDA Approves Belzutifan Plus Lenvatinib for Advanced Clear Cell RCC

The U.S. Food and Drug Administration (FDA) approved belzutifan (Welireg, Merck & Co., Inc.) in combination with lenvatinib (Lenvima, Eisai Inc.) on September 24, 2026, for adult patients with advanced renal cell carcinoma with a clear cell component (ccRCC).

This therapeutic combination is indicated for patients whose disease has progressed on or after treatment with a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor. Belzutifan is an oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, and lenvatinib is a multiple receptor tyrosine kinase inhibitor. The regulatory review utilized the FDA's Assessment Aid to facilitate application evaluation.

Clinical Efficacy Results From the LITESPARK-011 Trial

FDA approval was based on safety and efficacy data from LITESPARK-011 (NCT04586231), an open-label, randomized, active-controlled phase 3 clinical trial enrolling 747 patients with advanced ccRCC. Eligible participants presented with locally advanced or metastatic ccRCC that progressed on or after a PD-1 or PD-L1 inhibitor, or within six months of completing adjuvant therapy with a PD-1 inhibitor. Enrolled patients were randomized in a 1:1 ratio to receive either the combination of belzutifan and lenvatinib or cabozantinib monotherapy.

Dual major efficacy outcome measures were progression-free survival (PFS), assessed by blinded independent central review using RECIST v1.1, and overall survival (OS). Objective response rate (ORR) served as an additional efficacy outcome measure. Trial data demonstrated a statistically significant improvement in PFS for patients treated with belzutifan and lenvatinib compared to those receiving cabozantinib.

Median PFS was 14.6 months (95% CI: 11.1, 16.6) in the belzutifan plus lenvatinib arm versus 10.6 months (95% CI: 9.2, 11.1) in the cabozantinib arm (hazard ratio [HR] 0.74; 95% CI: 0.61, 0.89; one-sided p-value = 0.00095).
The objective response rate was 53% (95% CI: 47, 58) in the combination arm compared with 40% (95% CI: 35, 45) in the cabozantinib arm (one-sided p-value = 0.0002).

In the final analysis of overall survival, the difference between arms was not statistically significant. Median OS reached 33.7 months (95% CI: 29.0, 46.9) with belzutifan and lenvatinib compared to 28.6 months (95% CI: 24.1, 31.4) with cabozantinib (HR 0.85; 95% CI: 0.70, 1.03).

Key Clinical Takeaways for Oncology Nurses: Trial Efficacy and Outcomes

• Target Patient Eligibility: Confirm that patients have advanced or metastatic ccRCC that progressed on or after prior PD-1/PD-L1 checkpoint inhibitor therapy, or within six months of adjuvant PD-1 inhibitor completion.
• Statistically Significant PFS Extension: Combination therapy reduced the risk of disease progression or death by 26% compared to cabozantinib, achieving a median PFS of 14.6 months versus 10.6 months (HR 0.74; 95% CI: 0.61, 0.89; p = 0.00095).
• Elevated Objective Response Rate: Treatment with belzutifan plus lenvatinib produced a 53% ORR compared to 40% with single-agent cabozantinib (p = 0.0002).
• Overall Survival Findings: Median OS reached 33.7 months with the combination versus 28.6 months with cabozantinib, though final OS metrics did not achieve statistical significance (HR 0.85; 95% CI: 0.70, 1.03).

Recommended Dosing Schedule and Administration Parameters

The approved dosage for the combination regimen is 20 mg of lenvatinib taken orally in combination with 120 mg of belzutifan taken orally once daily. Both medications should be administered continuously until disease progression or unacceptable toxicity occurs. Consistent daily administration at the same time each day helps maintain stable therapeutic plasma levels.

Comprehensive Safety Profile and Boxed Warnings

The prescribing information for belzutifan contains a Boxed Warning regarding embryo-fetal toxicity. Additional warnings and precautions for belzutifan include severe anemia and hypoxia. When belzutifan is administered in combination with lenvatinib, the prescribing information includes specific warnings for cardiac dysfunction.

Lenvatinib prescribing information encompasses multiple warnings and precautions across organ systems. These include hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal failure or impairment, proteinuria, and diarrhea. Additional risks include fistula formation and gastrointestinal perforation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome (RPLS), hemorrhagic events, thyroid dysfunction, impaired wound healing, osteonecrosis of the jaw, and embryo-fetal toxicity.

Key Clinical Takeaways for Oncology Nurses: Toxicity Monitoring and Patient Care

• Embryo-Fetal Toxicity Screening: Both agents carry Boxed Warnings or severe warnings for embryo-fetal toxicity; verify pregnancy status prior to treatment and counsel female and male patients regarding mandatory effective contraception.
• Anemia and Hypoxia Surveillance: Monitor complete blood counts and oxygen saturation levels regularly to identify and manage belzutifan-induced anemia and hypoxia, initiating oxygen therapy or dose modifications as required.
• Cardiovascular and Blood Pressure Management: Perform routine blood pressure assessments, baseline and periodic electrocardiograms, and cardiac function evaluations to manage hypertension, cardiac dysfunction, and QT prolongation.
• Gastrointestinal and Renal Monitoring: Evaluate patients for severe diarrhea, proteinuria, elevated serum creatinine, and signs of gastrointestinal perforation or mucosal fistula formation.
• Adverse Reaction Reporting: Report suspected severe adverse reactions to the FDA MedWatch Reporting System or contact the Oncology Center of Excellence Project Facilitate team at 240-402-0004.

Reference

• U.S. Food and Drug Administration. FDA approves belzutifan in combination with lenvatinib for advanced renal cell carcinoma with a clear cell component. Published 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