Merck Announces the Presentation of Results from the Pivotal Phase 3 Litespark-022 Trial Evaluating Keytruda

Merck announced the first presentation of results from the Phase 3 LITESPARK-011 trial evaluating the dual oral regimen of WELIREG® (belzutifan), Merck?s first-in-class oral hypoxia-inducible factor-2 alpha (HIF-2a) inhibitor, plus LENVIMA® (lenvatinib), an orally available multiple receptor tyrosine kinase inhibitor (TKI) discovered by Eisai, for the treatment of patients with advanced renal cell carcinoma (RCC) whose disease progressed on or after treatment with anti-programmed death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy. These data are being presented as a late-breaking oral abstract at the 2026 American Society of Clinical Oncology (ASCO) Genitourinary (GU) Cancers Symposium (abstract #LBA417) and are included in the official ASCO GU Press Program. At a pre-specified interim analysis with a median follow-up of 29.0 months (range, 19.3-49.2), WELIREG plus LENVIMA demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint of progression-free survival (PFS), reducing the risk of disease progression or death by 30% (HR=0.70 [95% CI, 0.59-0.84]; p=0.00007) compared to cabozantinib.

For WELIREG plus LENVIMA, the median PFS was 14.8 months (95% CI, 11.2-16.6) versus 10.7 months (95% CI, 9.2-11.1) for cabozantinib. A trend toward improvement in overall survival (OS), the trial?s other primary endpoint, was also observed for WELIREG plus LENVIMA (HR=0.85 [95% CI, 0.68-1.05]; p=0.06075). The median OS was 34.9 months (95% CI, 27.5-NR) for WELIREG plus LENVIMA versus 27.6 months (95% CI, 24.0-31.4) for cabozantinib.

The trial is continuing, and OS will be evaluated at a subsequent analysis per the clinical trial protocol. Based on data from the LITESPARK-011 trial, the U.S. Food and Drug Administration (FDA) has accepted two supplemental New Drug Applications (sNDA) for review seeking approval for WELIREG plus LENVIMA for the treatment of adult patients with advanced RCC with a clear cell component following a PD-1 or PD-L1 inhibitor. The FDA set a Prescription Drug User Fee Act (PDUFA), or target action date, of October 4, 2026 for both the WELIREG and LENVIMA sNDAs.

Merck and Eisai will also discuss these data with regulatory authorities worldwide to support potential submissions outside the United States. Data for objective response rate (ORR) and duration of response (DOR), two key secondary endpoints, were also reported. At the first interim analysis with a median follow-up of 19.6 months (range, 9.9-39.8), WELIREG plus LENVIMA met ORR, demonstrating a statistically significant improvement compared to cabozantinib.

A confirmed ORR of 52.6% (95% CI, 47.3-57.7) was observed for WELIREG plus LENVIMA versus 39.6% (95% CI, 34.6-44.8) for cabozantinib. At the second interim analysis with a median follow-up of 29.0 months, the median DOR was 23.0 months (95% CI, 2.0-44.3+) for WELIREG plus LENVIMA versus 12.3 months (95% CI, 1.8+-35.9+) for cabozantinib. WELIREG plus LENVIMA was administered to 370 patients and cabozantinib was administered to 371 patients.

Grade =3 treatment-related adverse events (TRAEs) occurred in 71.6% of patients receiving WELIREG plus LENVIMA versus 65.8% of patients receiving cabozantinib. Adverse events led to the discontinuation of 11.1% of patients receiving WELIREG plus LENVIMA versus 11.3% of patients receiving cabozantinib, respectively. Serious adverse events were observed in 51.6% of patients receiving WELIREG plus LENVIMA versus 43.9% of patients receiving cabozantinib, and AEs led to death in 5.4% of patients (two were treatment-related: thrombotic microangiopathy [n=1] and pneumonitis [n=1]) versus 3.2% (one was treatment-related: hemoptysis [n=1]) of patients, respectively.

LITESPARK-011 is part of a comprehensive late-stage clinical development program for WELIREG comprised of several Phase 2 and Phase 3 trials in pheochromocytoma and paraganglioma, von Hippel-Lindau disease-associated neoplasms and RCC. The Phase 3 LITESPARK-012 trial is evaluating the addition of WELIREG to KEYTRUDA® (pembrolizumab), Merck?s anti-PD-1 therapy, plus LENVIMA in the first-line advanced RCC disease setting. WELIREG is approved [1] in the U.S., European Union (EU), Japan and other countries for the treatment of adult patients with advanced clear cell RCC following a PD-1/PD-L1 inhibitor and 1-2 VEGF-TKIs based on results from the Phase 3 LITESPARK-005 trial.

KEYTRUDA plus LENVIMA is approved in the U.S., the EU, Japan and other countries for the treatment of advanced RCC. Lenvatinib is approved as KISPLYX for advanced RCC in the EU. LENVIMA in combination with everolimus is approved in the U.S., EU and other regions for the treatment of adult patients with advanced RCC following one prior anti-angiogenic therapy.

Dr. Motzer has provided consulting and advisory services for Merck and Eisai.