Abstract 2090: Targeting HER family signaling in gastric cancer: The selective and equipotent EGFR, HER2 and HER3 signaling inhibitor, AZD8931, is efficacious in primary models of HER family driven disease.
Authors: Gavine Paul R. , Xie Liang , Zhang Lin , Lv Jing , Han Lu , Yin XiaoLu , Liu Yuan Jie , Su Xinying , Fan Shuqiong , Klinowska Teresa 
Published: August 2014

Despite an overall decline, gastric cancer incidence remains high in Asian countries including China, Japan and South 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. In advanced disease, the TOGA trial provided clinical validation of a role for HER2 in driving tumor progression in a subset of gastric cancer (GC) patients. However, recent clinical studies with EGFR targeting antibodies in GC have failed to show promise (EXPAND and REAL3 trials). Nonetheless, the dismal prognosis associated with late stage disease and the frequent implication of dysregulated HER family signaling in GC necessitate further investigation.

AZD8931 is an orally bioavailable, highly selective and potent small molecule inhibitor of EGFR, HER2 and HER3 signaling(1).

To evaluate the potential utility of this agent in clinical GC, we examined HER family gene amplification and expression in GC tissue samples and sought to correlate these profiles with response to AZD8931 in GC tumor xenograft models. High Her2 expression (IHC3+ or IHC2+/FISH+ve) was confirmed in 17.4% of tumours (20/115). Importantly, high level EGFR (44.4%, 48/108) and HER3 (89.3%, 92/103) protein expression was also detected in our cohort of Chinese GC samples. Gastric cancer cell panel screening (n=25 lines) identified a number of AZD8931-sensitive cell lines with a range of HER family expression profiles (GI50 range 0.02 to 0.35μM). In the NUGC3 xenograft model (high EGFR expression), twice-daily oral dosing of AZD8931 elicited potent, dose-responsive anti-tumour activity at well-tolerated doses (98% TGI at 6mg/kg/bid, 108% TGI at 12.5mg/kg/bid, all P&lt;0.0001) and anti-tumour efficacy correlated well with pharmacodynamic modulation of phospho-HER signaling. To investigate the translational relevance of these data, primary GC models with varying HER family protein expression profiles were identified and established. Within these models, AZD8931 anti-tumor efficacy correlated broadly with strong HER pathway activation (0 to 83% TGI at 12.5mg/kg/bid). We further evaluated the activity of AZD8931 in combination with cisplatin/5-FU, 1st line standard of care chemotherapies commonly used in the treatment of gastric cancer. Using a primary GC xenograft model, AZD8931 demonstrated additive benefit when used at well tolerated doses (minimal body weight loss). These data support the potential clinical utility of AZD8931 for the therapeutic treatment of gastric cancers exhibiting strong HER pathway signaling.

1 Hickinson et al. Clin.Cancer Res 2010; Feb 15.

Citation Format: Paul R. Gavine, Liang Xie, Lin Zhang, Jing Lv, Lu Han, XiaoLu Yin, Yuan Jie Liu, Xinying Su, Shuqiong Fan, Teresa Klinowska. Targeting HER family signaling in gastric cancer: The selective and equipotent EGFR, HER2 and HER3 signaling inhibitor, AZD8931, is efficacious in primary models of HER family driven disease. [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 2090. doi:10.1158/1538-7445.AM2013-2090