ODM-203 a selective inhibitor of FGFR and VEGFR, shows strong anti-tumor activity, and induces anti-tumor immunity.

Alterations in the gene encoding for the fibroblast growth factor receptor (FGFR) and upregulation of the vascular endothelial growth factor receptor (VEGFR) are found often in cancer, which correlate with disease progression and unfavorable survival. Additionally, FGFR and VEGFR signaling synergistically promote tumor angiogenesis, and activation of FGFR signaling has been described as functional compensatory angiogenic signal following development of resistance to VEGFR inhibition. Several selective small-molecule FGFR kinase inhibitors are currently in clinical development. ODM-203 is a novel, selective and equipotent inhibitor of the FGFR and VEGFR families. In this report we show that ODM-203 inhibits FGFR and VEGFR family kinases selectively and with equal potency in the low nanomolar range (IC50 6-35 nM) in biochemical assays. In cellular assays, ODM-203 inhibits VEGFR-induced tube formation (IC50 33 nM) with similar potency as it inhibits proliferation in FGFR-dependent cell lines (IC50 50-150 nM). In vivo, ODM-203 shows strong anti-tumor activity in both FGFR-dependent xenograft models and in an angiogenic xenograft model at similar well-tolerated doses. In addition, ODM-203 inhibits metastatic tumor growth in a highly angiogenesis-dependent kidney capsule syngenic model. Interestingly, potent anti-tumor activity in the subcutaneous syngenic model correlated well with immune modulation in the tumor microenvironment as indicated by marked decrease in the expression of immune check points PD-1 and PD-L1 on CD8 T cells and NK cells, and increased activation of CD8 T cells. In summary, ODM-203 shows equipotent activity for both FGFR and VEGFR kinase families and antitumor activity in both FGFR- and angigogenesis- models.