Combination of Belzutifan and Zanzalintinib versus Belzutifan alone in Patients with Advanced Renal Cell Carcinoma Who Have Received Prior Treatment (LITESPARK-034)

Renal cell carcinoma is the most common form of kidney cancer. In advanced stages of the disease, the tumor may no longer be operable or may have already spread to other parts of the body. At this stage, immunotherapies and targeted therapies are used. Treatment with the drug belzutifan is one such targeted therapy that specifically interferes with the growth and spread of certain cancer cells, and is already part of the standard of care as monotherapy for certain patients with advanced renal cell carcinoma. Zanzalintinib is another targeted anticancer drug from the class of tyrosine kinase inhibitors (TKIs). It simultaneously blocks several proteins that drive tumor growth, the formation of new blood vessels, and the spread of cancer cells. Zanzalintinib is not yet approved for the treatment of renal cell carcinoma and will be used in combination with belzutifan in this study.

The goal of the Phase 3 trial is to investigate whether the combination of belzutifan and zanzalintinib, compared to belzutifan alone, can delay disease progression (progression-free survival, PFS) and improve survival (overall survival, OS) in patients with advanced renal cell carcinoma. To this end, patients will be randomly assigned to two groups. The treatment arm receives belzutifan together with zanzalintinib, while the control arm receives belzutifan together with a placebo. Both medications are taken as tablets. Treatment is scheduled to last approximately 24 months. The study is double-blind, meaning that neither the patients nor the study physicians know who is receiving zanzalintinib in addition to belzutifan and who is receiving the placebo. In addition, disease progression will be assessed through an independent, blinded central radiological review. A total of approximately 758 patients are expected to participate in the study.

Eligible participants are patients aged 18 years or older with inoperable, advanced clear-cell renal cell carcinoma (RCC) at stage IV according to the American Joint Committee on Cancer (8th edition), with or without sarcomatoid components. A prerequisite is that the disease has progressed despite prior immunotherapy (targeted against PD-1/PD-L1) and targeted therapy against the growth factor VEGF. In total, no more than three prior drug therapies for renal cell carcinoma may have been administered, including no more than one immunotherapy targeting PD-1/PD-L1.