sitravatinib + nivolumab + ipilimumab

Sitravatinib + nivolumab + ipilimumab is an investigational triple combination regimen that includes sitravatinib, a small molecule tyrosine kinase inhibitor; nivolumab, a PD-1 immune checkpoint inhibitor monoclonal antibody; and ipilimumab, a CTLA-4 immune checkpoint inhibitor monoclonal antibody. Sitravatinib inhibits TYRO3, AXL, MERTK, VEGFR family, c-Kit, and c-Met, thereby modulating the tumor microenvironment and facilitating immune response. Nivolumab blocks PD-1 on T cells to prevent immune evasion by tumor cells, and ipilimumab blocks CTLA-4 to further enhance anti-tumor T cell activity. The combination seeks to potentiate immunotherapy responses and overcome resistance seen with dual immune checkpoint therapy, particularly in advanced clear cell renal cell carcinoma. Phase I data show an objective response rate of 45.5% and disease control rate of 86.4% in previously untreated advanced ccRCC, with median progression-free survival of 14.5 months. Mechanistic studies indicate dynamic shifts in the tumor microenvironment, including increased T cell infiltration, decreased myeloid and endothelial cells, and features of resistance such as T cell exhaustion and epithelial-mesenchymal transition[1][2][3].