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Background: Zanzalintinib (XL092) is a novel, potent, orally bioavailable small molecule inhibitor of several receptor tyrosine kinases, including VEGFR2, MET, and the TAM kinases AXL, and MER. These receptor tyrosine kinases are implicated in several oncogenic processes, including tumor angiogenesis, proliferation, invasion, and metastasis. MET and AXL are known to play important roles in the development of resistance to antiangiogenic therapies. In addition, drugs targeting the TAM kinases are thought to promote an immune-permissive environment, potentially enhancing responses to immune checkpoint inhibitors (ICIs). This hypothesis has been confirmed in preclinical murine tumor models in which zanzalintinib in combination with an anti–PD-1 agent showed significantly greater antitumor and immunomodulatory activity, as well as a greater survival benefit, when compared with either agent alone (Hsu J, et al. Mol Cancer Ther 2023). In a phase 1 first-in-human study, zanzalintinib alone or in combination with atezolizumab showed a manageable safety profile and a half-life of 16–22 hours for zanzalintinib supporting once-daily dosing. The combination also showed promising clinical activity in patients with advanced or metastatic solid tumors, including renal cell carcinoma (RCC; Sharma MR, et al. ESMO 2022:Abs 481P). The encouraging preclinical and clinical activity support the evaluation of zanzalintinib in combination with ICIs in clinical studies, including STELLAR-304 (NCT05678673), a randomized study that is exploring the efficacy and safety of zanzalintinib in combination with nivolumab in patients with non-clear cell RCC (nccRCC). STELLAR-002 (NCT05176483) is another ongoing study assessing the safety and preliminary efficacy of zanzalintinib in multiple ICI combinations in patients with advanced solid tumors. Presented here is the study design of the cohort-expansion stage for patients with RCC in STELLAR-002. Methods: STELLAR-002 is a multicenter, open-label, phase 1b trial consisting of a dose-escalation stage and a tumor-specific cohort-expansion stage. The study is enrolling adults who have a cytologically or histologically confirmed solid tumor that is unresectable, locally advanced, or metastatic. In addition, patients with RCC enrolled in the expansion phase must have measurable disease per RECIST v1.1 as assessed by the investigator. The recommended doses of zanzalintinib plus nivolumab, zanzalintinib plus nivolumab and ipilimumab, and zanzalintinib plus nivolumab and relatlimab are being established in the dose-escalation stage of the study. The study includes three dose-expansion cohorts for patients with RCC: first-line clear cell RCC (ccRCC; Cohort 1), second-line ccRCC after 1 prior ICI-based combination therapy (Cohort 2), and first-line nccRCC (Cohort 6). The following regimens are available options for randomization at the recommended dose depending on the cohort: single-agent zanzalintinib (Regimen A), zanzalintinib plus nivolumab (Regimen B), zanzalintinib plus nivolumab and ipilimumab (Regimen C), or zanzalintinib plus nivolumab and relatlimab (Regimen D). Patients in Cohort 1 may be randomized to Regimens B, C, or D, patients in Cohort 2 to Regimens A, B, or D, and patients in Cohort 6 to Regimens A or B. The primary objectives of the cohort-expansion stage are objective response rate per RECIST v1.1 (as assessed by the investigator) and incidence and severity of adverse events, including serious and immune-mediated events. The trial is ongoing and enrolling patients from 13 countries in North America, Europe, and the Asia-Pacific region. [ABSTRACT FROM AUTHOR]