STELLAR-304: a phase III study of zanzalintinib (XL092) plus nivolumab in advanced non-clear cell renal cell carcinoma

Abstract

Management of advanced non-clear cell renal cell carcinoma (nccRCC) is challenging due to disease rarity and heterogeneity. The combination of multi-targeted tyrosine kinase inhibitor (TKI) with immune checkpoint inhibitor (ICI) has emerged as an effective treatment strategy, but well-designed, phase III randomized clinical trials are needed to demonstrate superiority over current treatment options. Zanzalintinib is a novel, multi-targeted TKI that has demonstrated promising preclinical anti-tumor activity in combination with ICIs. STELLAR-304 is a phase III trial evaluating first-line zanzalintinib plus nivolumab versus sunitinib in advanced nccRCC. Primary endpoints are progression-free survival and objective response rate. Secondary endpoint is overall survival. To our knowledge, STELLAR-304 is the first phase III study assessing a TKI-ICI combination in nccRCC patients across multiple subtypes.Clinical Trial Registration: This trial is registered at ClinicalTrials.gov (identifier: NCT05678673).; Advanced non-clear cell renal cell carcinoma (nccRCC) is a group of rare kidney cancers that have spread to other parts of the body. Currently available treatment options for nccRCC are based on results from phase II studies for nccRCC involving small numbers of patients or from studies conducted for all kidney cancers; these treatments may not adequately control the disease. Therefore, new and effective therapies are urgently needed. Zanzalintinib is an investigational oral drug that may reduce or stop cancer cells from growing and spreading. Zanzalintinib may also improve how well the body responds to another type of cancer drug called immune checkpoint inhibitor (ICI), which works by helping the body’s own immune system attack cancer cells. STELLAR-304 is a global, phase III study in people who have not been previously treated for advanced nccRCC. The study will test how zanzalintinib plus nivolumab, an ICI, can control the disease compared with sunitinib, a therapy commonly used to treat nccRCC. Participants will be randomly assigned in a 2 to 1 ratio to receive either zanzalintinib plus nivolumab or sunitinib. We will compare how long participants stay alive without nccRCC worsening and evaluate how their tumor responds to the two study treatments. Additionally, we will monitor the side effects in the treatment groups. Approximately 291 participants will be included.