Abstract 928: Volitinib (HMPL504), a novel, selective and potent cMET inhibitor, is efficacious in primary tumor models of cMET-driven gastric cancer.
Authors: Gavine Paul R. , Fan Shiming , Fu Haihua , Han Lu , Liu Yuan Jie , Lv Jing , Qing Weiguo , Ren Yongxin , Su Weiguo , Su Xinying , Wang Huiying , Xie Liang , Xu Shirlian , Xu Wen , Yin XiaoLu , Yu Yongjuan , Zhang Tianwei , Wang Q.May 
Published: August 2014

Gastric cancer (GC) incidence rates are amongst the highest in Asian countries including; China, Japan and Korea(1). 5-year survival rates in early stage disease have improved through aggressive combinations of surgery and chemo/radiotherapy. In late stage disease however, despite Her2 molecular segmentation and trastuzumab therapy, prognosis remains dismal and novel therapeutic options are urgently required(2).

The MET oncogene encodes the receptor tyrosine kinase for hepatocyte growth factor and controls genetic programs leading to cell growth, invasion and survival. Dysregulation of MET signaling is a common feature of a diverse range of human tumor types and thus represents a highly competitive and attractive therapeutic target. Volitinib (HMPL-504) is an orally bioavailable, highly selective and potent small molecule ATP-competitive inhibitor, which inhibits cMET autophosphorylation and downstream signaling (3). Volitinib is currently in Phase I clinical development. To evaluate the utility of volitinib in treating patients with GC, we established the incidence of cMET amplification and overexpression and attempted to correlate this with response to volitinib in primary GC tumor models. Elevated cMET gene copy number (amplification 5%, high polysomy 13%), and protein overexpression (12%, cases &gt; IHC 2+, 16% &gt; IHC1+) were detected in a cohort of 217 Chinese GC samples using fluorescent in situ hybridization (FISH) and immunohistochemical (IHC) approaches. In vitro proliferation assays were performed on a panel of 26 GC cell lines and profound sensitivity to volitinib was demonstrated in lines harboring elevated cMET gene copy number (GI50 range 6 to 49nM). In the cMET amplified GC xenograft model, Hs746t, once-daily oral dosing of volitinib (2.5mg/kg) elicited potent anti-tumour activity at well-tolerated doses (97% tumour growth inhibition after 16 days dosing, P&lt;0.0001) which correlated well with pharmacodynamic modulation of phospho-cMET signaling. To strengthen the translational relevance of these data, a panel of cMET amplified primary GC models were identified and established. In these models, volitinib demonstrated potent tumor growth inhibition or regressions (90% and 84% TGI at 10mg/kg/qd, all P&lt;0.0001), correlated with pharmacodynamic modulation of tumor phospho-cMET. In contrast, 10mg/kg/qd volitinib was inactive (18% TGI, P=0.2405) in a cMET non-amplified control model. We also evaluated the activity of volitinib in combination with docetaxel, a standard of care chemotherapeutic commonly used in the treatment of gastric cancer. In model Hs746t, volitinib demonstrated additive benefit when used with docetaxel at well tolerated doses. These data support the potential clinical utility of volitinib as a selective agent for the therapeutic treatment of gastric cancers harboring dysregulated cMET signaling.

Citation Format: Paul R. Gavine, Shiming Fan, Haihua Fu, Lu Han, Yuan Jie Liu, Jing Lv, Weiguo Qing, Yongxin Ren, Weiguo Su, Xinying Su, Huiying Wang, Liang Xie, Shirlian Xu, Wen Xu, XiaoLu Yin, Yongjuan Yu, Tianwei Zhang, Q.May Wang. Volitinib (HMPL504), a novel, selective and potent cMET inhibitor, is efficacious in primary tumor models of cMET-driven gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 928. doi:10.1158/1538-7445.AM2013-928