A Biomarker Study Of Lapatinib In The Neoadjuvant Treatment Of Her2 Over Expressing Esophago-Gastric Adenocarcinoma (Ega)

Introduction 16% of EGA over-express HER2 and Trastuzumab with chemotherapy improves survival in metastatic patients. Lapatinib, a dual EGFR and HER2 inhibitor has shown disappointing results in EGA, and in vitro studies suggest MET, IGFR and HER3 confer resistance. This trial investigated the toxicity of neoadjuvant lapatinib plus chemotherapy, feasibility of additional endoscopy for biomarker endpoints and molecular biomarkers to elucidate resistance mechanisms in vivo. Methods Patients with operable HER2 over expressing EGAs (IHC3+ or IHC2+ with FISH amplification) were treated with 10 days of lapatinib (1250mg od). PET imaging and biopsies were done at D0 and D10. 3 cycles (q21) of Capecitabine (850mg/m2 bd D1-14) and Oxaliplatin (130mg/m2 D1) were then given, followed by surgery at D108-115. The Collaborative Enhanced Reactive Immunoassay (CEER) assessed receptor activation and downstream signalling. A D0 biopsy was treated ex vivo with lapatinib and formalin fixed for drug sensitivity assessment by P-HER2 immunohistochemistry (IHC). The trial was powered to assess for molecular endpoints (n = 13). Results The trial closed early due to anastamotic leaks in 2/10 for which a drug effect could not be excluded. Lapatinib monotherapy did not cause Grade3+ toxicity, whilst toxicities during chemotherapy were as expected, except for grade3+ diarrhoea (20%). The ex vivo and D10 P-HER2 IHC showed on target effects (77%) with good correlation (k0.63). PI3K (p = 0.0037) and Erk (p = 0.005) activation correlated with MET activation, but not with IGFR or HER3. A molecular response did not correlate with D10 PET (no response seen), radiological or pathological responses (1 CPR), although median overall survival has not been reached. Conclusions In view of the leak-rate a longer washout period prior to surgery should be considered. Real-time biomarker assays on endoscopic biopsies are feasible. MET appears to be a significant in vivo mechanism of resistance and may represent a therapeutic target. Citation Format: Nadeera K. De Silva, Laura Schulz, Anna Paterson, Tara Nuckcheddy-Grant, Wendi Qain, Edmund Godfrey, Heok Cheow, Maria O9Donovon, Minesh Jobanputra, Daniel Hochhauser, Rebecca C. Fitzgerald, Hugo Ford. A biomarker study of lapatinib in the neoadjuvant treatment of HER2 over expressing esophago-gastric adenocarcinoma (EGA). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3596. doi:10.1158/1538-7445.AM2015-3596