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.