Abstract B4: Regorafenib: a new oral multikinase inhibitor of angiogenic, stromal and oncogenic (receptor tyrosine) kinases with potent preclinical antitumor activity

Angiogenesis is a critical driver of tumor growth and progression, and is controlled by a number of interconnected signaling pathways. In these pathways, the two tyrosine kinase receptors, vascular endothelial growth factor receptor (VEGFR) 2 and tyrosine kinase with immunoglobulin and EGF homology domain 2 (TIE2) play crucial roles in the neovascularization, stabilization, and maintenance of normal and tumor vasculature. Regorafenib, a novel oral multikinase inhibitor, potently inhibits both VEGFR2 and TIE2 in biochemical and cellular kinase phosphorylation assays. It inhibits additional angiogenic kinases ie VEGFR1, VEGFR3, platelet‐derived growth factor receptor‐ , and fibroblast growth factor receptor‐1 and the mutant oncogenic kinases KIT and RET, which play a role in human gastrointestinal stromal and thyroid cancers, respectively, and B‐RAF. The mechanism of action of regorafenib on the tumor vasculature was demonstrated in vivo by dynamic contrast‐enhanced magnetic resonance imaging using Gadomer as contrast agent. Regorafenib significantly decreased tumor perfusion and extravasation of the contrast agent in a rat GS9L glioblastoma tumor xenograft model grown i.m. in the rat leg compared to rat muscle tissue after a single oral administration of 10 mg/kg. The pharmacodynamic effects persisted for 48 hours after the last drug administration and correlated with the tumor growth inhibition in a QDx4 once daily oral dosing study. A significant reduction in tumor microvessel area was observed in a human colorectal xenograft after QDx5 daily oral dosing at 10 and 30 mg/kg of regorafenib in tumor‐bearing mice. Regorafenib exhibited potent dose‐dependent tumor growth inhibition in various preclinical murine xenograft models including breast (MDA‐MB‐231), NSCLC (NCI‐H460), renal (786‐O), and several colorectal (Colo‐205, HCT‐15, HT‐29) carcinoma, some of which carry mutant K‐RAS and/or B‐RAF. Tumor shrinkage was observed in the breast MDA‐MB‐231 and the renal 786‐O carcinoma models. The compound was well tolerated and no significant weight loss or lethality was observed. Immunohistochemical analyses of the breast xenograft tumor revealed a strong reduction in staining of the proliferation marker Ki‐67 and of the phosphorylated extracellular regulated kinases 1 and 2. Non‐clinical metabolism studies have detected two pharmacokinetically stable regorafenib metabolites, with similar but distinct kinase profiles. These data demonstrate that regorafenib is a well‐tolerated, orally active multikinase inhibitor with a unique target profile that may have therapeutic benefit in human malignancies. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B4.