Peng Peng¹, Lihua Yu¹, Xiaoju Yang¹, Haiyan Zhou¹, Yan Hu², Taiping Chen², Chengkon Shih¹, Frank Wu¹

¹Biology, XuanZhu Pharma, ²In Vivo Pharmacology, Viva Biotech

Objective:Despite the improved patient care and the declined mortality rate, gastric cancer is still a leading cause of cancer deaths worldwide, particularly in Asia. Recent comprehensive molecular characterization of gastric adenocarcinoma has not only revealed the molecular mechanisms underlining the progression of gastric cancer, but also provided aroadmap for personalized therapies. ErbB family is among the mostly-mutated oncogenes in gastric adenocarcinoma. Pirotinib, a novel irreversible tyrosine kinase inhibitor, has demonstrated highly effective anti-tumor activities against mutations in EGFR, ErbB2, and ErbB3, suggesting its clinical value in treatment of gastric cancer, potentially guided by genetic screening. Method:11 naïve Asian patient-derived xenograft (PDX) gastric adenocarcinoma models were investigated using pirotinib. The tumor burden was established subcutaneously in Balb/c nude mice. Once the mean tumor size reached approximately 150mm³, pirotinib was orally administrated at 20mg/kg once daily for 3 weeks. Routine monitoring to record the mobility, abnormal activity, body weight, and tumor size was performed during the study. At the end of the treatment, individual mouse was sacrificed and the tumor size was measured, and the tumor growth inhibition (TGI) was calculated. Result: Among the 11 PDXs tested, strong efficacy has been observed in 3 models with 76.3% to 80.3% TGI; approximately 50% TGI was seen in another 5 models. Conclusion: Pirotinib demonstrated strong anti-tumor efficacy in the 11 PDX gastric adenocarcinoma models. The next generation sequencing of the tumor tissues was performed. Additional analysis might help reveal useful biomarkers that may predict treatment sensitivity in patients in the ongoing clinical trial of pirotinib.

Key Words: Gastric cancer  ErbB  Tyrosine kinase inhibitor