U.S. Food and Drug Administration (FDA) has approved the dual oral regimen of WELIREG® (belzutifan), Merck’s first-in-class oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, plus LENVIMA® (lenvatinib), the orally available multiple receptor tyrosine kinase inhibitor (TKI) discovered by Eisai, for the treatment of adult patients with advanced renal cell carcinoma with a clear cell component (ccRCC) following a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor.

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The approval is based on data from the Phase 3 LITESPARK-011 trial. Results from a pre-specified interim analysis showed treatment with WELIREG plus LENVIMA led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS), one of the dual primary endpoints, compared to cabozantinib, reducing the risk of disease progression or death by 26% (HR=0.74 [95% CI, 0.61-0.89]; p=0.001) in patients with advanced ccRCC following a PD-1 or PD-L1 inhibitor. WELIREG plus LENVIMA resulted in a median PFS of 14.6 months (95% CI, 11.1-16.6) versus 10.6 months (95% CI, 9.2-11.1) with cabozantinib. WELIREG plus LENVIMA also demonstrated a statistically significant improvement in objective response rate (ORR), a key secondary endpoint, with an ORR of 53% (95% CI, 47-58) versus 40% (95% CI, 35-45) for cabozantinib (p=0.0002). Data for duration of response (DOR), another secondary endpoint, were also reported. At the final analysis, overall survival (OS), the study’s other primary endpoint, did not meet statistical significance for patients who received WELIREG plus LENVIMA versus cabozantinib. These results will be presented at the upcoming European Society for Medical Oncology (ESMO) Congress 2026 in Madrid, Spain.

The WELIREG prescribing information contains a boxed warning that exposure to WELIREG during pregnancy can cause embryo-fetal harm. Verify pregnancy status prior to the initiation of WELIREG. Advise patients of these risks and the need for effective non-hormonal contraception. WELIREG can render some hormonal contraceptives ineffective. WELIREG can cause severe anemia that can require a blood transfusion. Monitor for anemia before initiation of and periodically throughout treatment with WELIREG. WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen or hospitalization. Monitor oxygen saturation before initiation of and periodically throughout treatment with WELIREG. Serious cardiac dysfunction, including heart failure with reduced left ventricular ejection fraction (LVEF), and cardiomyopathy, can occur with WELIREG in combination with LENVIMA. The safety of WELIREG in combination with LENVIMA has not been established in patients with LVEF below 50%. Monitor patients for symptoms or signs of heart failure and if present, reassess LVEF. Withhold and resume at a reduced dose upon recovery to baseline or Grade 1 or permanently discontinue WELIREG in combination with LENVIMA based on severity. For more information, see "Selected Safety Information" below.

Adverse reactions, some of which can be serious or fatal, may occur with LENVIMA, including hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal failure or impairment, proteinuria, diarrhea, fistula formation and gastrointestinal perforation, QTc interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid stimulating hormone suppression/thyroid dysfunction, impaired wound healing, osteonecrosis of the jaw and embryo-fetal toxicity. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should be advised to use effective contraception, and based on the severity of the adverse reaction, LENVIMA should be interrupted, reduced and/or discontinued. For more information, see "Selected Safety Information" below.