Bozitinib, A Highly Selective Inhibitor Of Cmet, Demonstrates Robust Activity In Gastric, Lung, Hepatic And Pancreatic In Vivo Models

Background: cMET is a receptor tyrosine kinase that is located on the cell surface and is activated by the binding of its ligand, hepatocyte growth factor (HGF). In cancer cells, MET can be aberrantly active and cause abnormal signaling, which leads to tumor growth, angiogenesis, and metastasis. In vitro studies have demonstrated that bozitinib (CBT-101, PLB-1001) is a highly selective and specific inhibitor (8 nM) of tumor cell proliferation. Methods: In-vivo PD studies of gastric (MKN45), lung (LUM858, LU1901, LU2503), hepatic (LIM0612, LIM0801), and pancreatic (KP4) were evaluated. These models covered both the HGF-dependent and HGF-independent mechanisms. Among these models, LUM858, LU1901, LU2503, LIM0612 and LIM0801 are PDX models. In particular, in the LU1901 model, bozitinib (BT) was compared to capmatinib (INC280). Groups included: BT at 1, 3 and 10 mg/kg QD×21 and INC280 at 1, 3, and 10 mg/kg QD×21 and 10 mg/kg BID×21 via IG, CDDP 5 mg/kg, Q7D×3 as a positive control via IP and the vehicle control (QD×21 via IG). Each group (n=8 mice) and the tumor volume was evaluated on D21. Results: In MKN45, LU2503, LIM0612 and LIM0801, the effect of BT seemed superior than that of crizotinib; in LUM858, its effect was higher than that of erlotinib; in LU1901, its effect was higher than that of crizotinib and INC280. In the LU1901 model, the strongest activity was observed at BT 10 mg/kg with a T/C ratio of 2%, compared to an equi-dose of INC280 (T/C of 22%). All doses of BT and INC280 were well tolerated; no mouse experienced weight loss. In MKN45 model, BT showed a PK/PD correlation and dose-dependence. BT inhibited the phosphorylation of c-Met protein; the rate of target inhibition exceeded 90% at >7 mg/kg. The plasma concentration for BT decreased over time with a significant decrease 16h after its administration, conferring at least 16h of phosphorylation inhibition of the c-Met protein. Conclusions: In conclusion, BT was well-tolerated, with no animal death nor major weight loss. The in vivo experiments demonstrated that BT is a viable candidate with effective anti-tumor activities. BT is currently under evaluation in cMet dysregulated NSCLC (NCT02896231) with additional trials planned. Citation Format: Joe Shih, Boyu Zhong, Hepeng Shi, David Xue, Gavin S. Choy, Sanjeev Redkar. Bozitinib, a highly selective inhibitor of cMet, demonstrates robust activity in gastric, lung, hepatic and pancreatic in vivo models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2096. doi:10.1158/1538-7445.AM2017-2096