Activity Of Azd4547, A Potent And Selective Fgf-Receptor Inhibitor, Alone And In Combination With Chemotherapy In Standard Xenograft And Human Primary Explant Models Of Fgf-Receptor 2 Amplified Gastric Cancer

Abstract Despite an overall decline, gastric cancer incidence remains high in Asian countries including China, Japan and Korea. Five-year survival rates continue to improve in early stage disease through an aggressive combination of surgery and chemo/radiotherapy, primarily using fluoropyrimidine and platinum agent combinations. Furthermore, the ‘TOGA’ gastric cancer trial(1) has provided clinical validation of a role for Her2 in driving tumour progression in a subset of gastric cancer patients. Despite these advances, late stage disease continues to have a dismal prognosis and there remains an urgent need for novel therapeutic options. We have previously established the incidence of FGFR2 gene amplification in Chinese and Caucasian clinical gastric cancer tissues (∼4-7%) and have validated FGFR2 oncogene addiction in amplified gastric cancer cell lines, in vitro and in vivo, using both FGFR2 siRNA and a selective small molecule FGFR inhibitor, AZD4547(2). AZD4547 is an orally bioavailable, highly selective and potent small molecule inhibitor which competes with ATP for binding to FGF receptors 1, 2 and 3, thereby inhibiting autophosphorylation and downstream signalling. This agent is currently in Phase I clinical studies. To further evaluate the potential utility of AZD4547 in clinical gastric cancer, we established a bank of 19 gastric cancer primary explant models, derived directly from human tumour tissue. Characterisation of these models using FGFR2 fluorescent in-situ hybridisation analysis (FISH) identified an amplified model, SGC083, with corresponding high level FGFR2 protein expression. In this model, oral daily dosing of AZD4547 elicited rapid, potent and durable tumour regression at well-tolerated doses (197% tumour growth inhibition after 25 days dosing with 6.25mg/kg AZD4547, p=<0.0001). Anti-tumour efficacy correlated well with pharmacodynamic modulation of phospho-FGFR signaling. In contrast, in primary explant models lacking FGFR2 gene amplification, equivalent doses of AZD4547 were significantly less efficacious or inactive (26% and 7% tumour growth inhibition after 14 days dosing at 25mg/kg, p=0.03 and p=0.4 respectively). We also evaluated the activity of AZD4547 in combination with chemotherapeutics considered standard of care in the treatment of gastric cancer (5-FU, cisplatin, taxotere and capecitabine) in FGFR2 amplified models. AZD4547 exhibited efficacy benefit when used with chemotherapeutics at well tolerated doses (minimal body weight loss). These data support the potential clinical utility of AZD4547 as a selective agent for the therapeutic treatment of gastric cancers harbouring genetic amplification of FGFR2. 1 Van Cutsem et al. J Clin Oncol 2009;27:18s. 2 Xie et al. 2011 AACR Annual Meeting. Abstract 1643. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3758. doi:1538-7445.AM2012-3758