Merck and Eisai announced mixed results from their Phase 3 LITESPARK-011 trial evaluating the combination of WELIREG (belzutifan) and LENVIMA (lenvatinib) in patients with advanced renal cell carcinoma whose disease progressed following immunotherapy treatment.
The dual oral regimen met one of its primary endpoints, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival compared to cabozantinib (Cabometyx) in a pre-specified interim analysis. The combination also achieved a statistically significant improvement in objective response rate, with a higher proportion of patients experiencing substantial tumor reduction or complete disappearance compared to those treated with cabozantinib.
However, the combination failed to demonstrate statistical significance in overall survival, the study's other primary endpoint, at the time of this interim analysis. Overall survival will be evaluated in a subsequent analysis according to the clinical protocol.
Trial Design and Patient Population
The randomized, open-label Phase 3 trial enrolled approximately 708 patients with advanced clear cell renal cell carcinoma that had progressed on or after anti-PD-1/L1 therapy. Participants were randomly assigned to receive either WELIREG (120 mg orally once daily) plus LENVIMA (20 mg orally once daily) or cabozantinib (60 mg orally once daily).
"Despite recent treatment advances, many patients with advanced RCC may still experience disease progression following treatment with a PD-1/L1 inhibitor," said Dr. M. Catherine Pietanza, Vice President, Global Clinical Development, Merck Research Laboratories. "These positive results from LITESPARK-011 show the potential of this novel combination to reduce the risk of disease progression or death for patients who are in need of innovative options on or after treatment with immunotherapy."
Clinical Context and Significance
Renal cell carcinoma represents the most common type of kidney cancer, with approximately nine out of 10 kidney cancer diagnoses being RCC. In 2022, there were about 435,000 new cases of kidney cancer diagnoses and approximately 156,000 deaths from the disease worldwide. The condition affects men twice as commonly as women, typically between ages 60 and 70, with approximately 30% of patients diagnosed at an advanced stage.
The trial addresses a significant unmet medical need for patients whose cancer has progressed following immunotherapy, representing a challenging treatment scenario with limited effective options.
Drug Mechanisms and Safety Profile
WELIREG is Merck's first-in-class oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, while LENVIMA is an orally available multiple receptor tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors and other kinases implicated in tumor growth and cancer progression.
The safety profiles of both drugs in this trial were consistent with those observed in previously reported studies for the individual therapies, with no new safety signals identified.
Regulatory and Development Plans
Merck and Eisai plan to discuss these data with regulatory authorities worldwide and will present the findings at an upcoming medical meeting. The companies will continue to evaluate overall survival in subsequent analyses as outlined in the clinical protocol.
"We are encouraged by the data observed in the LITESPARK-011 trial, which bolster our belief in the role of LENVIMA in various combinations as a treatment option for patients impacted by advanced RCC," said Dr. Corina Dutcus, Senior Vice President, Oncology Global Clinical Development Lead at Eisai.
Broader Development Program
LITESPARK-011 is part of a comprehensive late-stage clinical development program for WELIREG, which includes several Phase 2 and Phase 3 trials in renal cell carcinoma, pheochromocytoma and paraganglioma, and von Hippel-Lindau disease-associated neoplasms. The Phase 3 LITESPARK-012 trial is currently evaluating the addition of WELIREG to KEYTRUDA (pembrolizumab) plus LENVIMA in the first-line advanced RCC setting.
WELIREG is currently approved in the United States, European Union, Japan, and other countries for treating 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.
