Background: Sitravatinib is a receptor tyrosine kinase inhibitor (RTKI) that targets multiple closely related RTK pathways including VEGFR, PDGFR, KIT, MET and the TAM receptors (TYRO3, AXL and MERTK) Nivolumab is a monoclonal antibody against PD-1 and releases PD-1-mediated inhibition of T-cell proliferation and cytokine production. Together, sitravatinib and nivolumab may cooperate to elicit greater anti-tumor activity than either agent alone, as sitravatinib is predicted to enhance several steps in the cancer immunity cycle that may augment nivolumab’s efficacy. Mechanisms by which sitravatinib may augment an antitumor immune response include enhanced antigen presentation; depletion of immunosuppressive regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) via inhibition of split kinases VEGFR and KIT; and shifting tumor-associated macrophages from an immunosuppressive M2 to a pro-immunogenic M1 phenotype via inhibition of TAM RTKs. Each of these factors converge on promoting T effector cell expansion, tumor infiltration and an antigen-specific anti-tumor immune response. Methods: This open-label, non-randomized, preoperative window of opportunity Phase 2 study evaluates tolerability and clinical activity of sitravatinib in combination with nivolumab in pts with locally-advanced ccRCC undergoing nephrectomy. Study treatment consists of 2 weeks of sitravatinib monotherapy followed by 4 weeks of the combination. Sitravatinib is administered orally daily at 120 mg; nivolumab intravenously every 2 weeks at 240 mg. The primary objective is to evaluate clinical activity using percentage of pts achieving a presurgical point-in-time objective response. Secondary objectives include evaluation of safety and tolerability, and determination of the immune effects of sitravatinib monotherapy and the combination through serial tissue and blood collections (temporal changes in PD-L1 expression, selected cytokines and immune cell populations including MDSCs, Tregs and ratio of M1:M2 macrophages). The study is open for enrollment and recruitment is ongoing. Clinical trial information: NCT03680521