Background: Cabozantinib, an inhibitor of MET, VEGFR2, AXL, and MER, has shown significant clinical activity in multiple solid tumors, both alone and in combination with immune checkpoint inhibitors (ICIs). XL092 has a similar target profile to cabozantinib but with a significantly shorter clinical half-life and pharmacokinetic properties suitable for once daily oral dosing (Hsu, Eur J Cancer, 2020). In preclinical studies, the combination of XL092 and anti–PD-1 exhibited greater anti-tumor activity than either agent alone. Here, we describe further preclinical characterization of XL092 in combination with ICIs, including modulation of immune cells in vivo and in vitro. Methods: Pharmacodynamic activity was evaluated in the MC38 syngeneic tumor model following treatment with XL092 alone or in combination with anti–PD-1 or anti–PD-L1. Tumor CD31+ microvessel density and CD8+ T cell infiltration were assessed by immunohistochemistry, and circulating immune cells were measured by FACS. Macrophage repolarization and efferocytosis were evaluated in vitro using primary human macrophages. Results: Treatment of MC38 tumor-bearing mice with XL092 inhibited tumor angiogenesis in a dose-dependent manner, and combination treatment with XL092 and anti–PD-1 increased CD8+ lymphocyte tumor cell infiltration compared with either agent alone. XL092 and ICIs also promoted significant changes in peripheral immune cell subsets in the MC38 model. Treatment with XL092 alone or in combination with ICIs increased circulating levels of CD4+ and CD8+ T cells and B cells, and combination treatment with anti–PD-1 decreased levels of proliferating and IFNg-producing effector T cells in circulation. While the level of peripheral NK cells was unaffected by these treatments, XL092 alone or in combination with ICIs decreased levels of proliferating and GrzB+ effector cells in circulation. Treatment with XL092 alone or in combination with ICIs reduced the levels of circulating myeloid cells, including myeloid-derived suppressor cells, dendritic cells, and macrophages. In vitro treatment of human macrophages with XL092 inhibited macrophage efferocytosis with IC50 ~81 nM and promoted repolarization from an M2 anti-inflammatory to an M1 pro-inflammatory phenotype. Conclusions: Immune cell profiling showed that treatment with XL092 and ICIs promotes CD8+ T cell tumor infiltration, increases in peripheral lymphocytes, decreases in peripheral myeloid cells, and macrophage repolarization, suggesting that XL092 promotes an immune-permissive tumor microenvironment. Consistent with these immunomodulatory effects, the combination of XL092 and ICIs has shown greater anti-tumor activity in syngeneic tumor models than either agent alone. XL092 is currently being evaluated in multiple solid tumors as a single agent and in combination with ICIs in the phase 1/1b STELLAR trials (NCT03845166).
Citation Format: Jeff Hsu, Colin Chong, Jeffrey Serrill, Sharon Wu, Kevin Leong, Ted Yun, Lynne Bannen, Peter Lamb, Wei Xu, Peiwen Yu. The tyrosine kinase inhibitor XL092 promotes an immune-permissive tumor microenvironment and enhances the anti-tumor activity of immune checkpoint inhibitors in preclinical models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P248.