Response to Cetuximab by ESCC PDXs Directly Correlate to EGFR Overexpression.

e15078 Background: Esophageal squamous cell carcinoma (ESCC) is a deadly malignance prevalent in parts of China and no target therapy option. Cetuximab, approved for treating subset of metastatic colorectal carcinoma (mCRC) and head and neck squamous cell carcinoma (HNSCC), has yet to be tested on ESCC. Patient derived xenografts (PDXs) are known to mimic original patient diseases, and thus their drug response. Methods: We created a cohort of ESCC PDXs and conducted a preclinical mouse clinical trial (MCT) assessing antitumor activity of cetuximab by randomly enrolling a cohort of 16 ESCC PDXs. We analyzed the drug activity using endpoints of both ORR (objective response rate per traditional TGI, tumor growth inhibition%, and clinical RECIST criteria) and survival per PFS (progression free survival) and OS (overall survival). Finally, we also investigated associated biomarker predictive of response through genomic profiling of these PDXs. Results: 12/16subjects responded to cetuximab with ORR of 75% per 60% TGI, with medium OS of 75 days for cetuximab vs. 46 days for control or medium PFS 59 days vs. 35 days respectively, all significant more than that in gastric carcinoma1. Microarrays/RNAseq revealed that the response is directly related to EGFR over-expression (r2=0.63, p-value <0.0003) (also gene amplification), similarity also seen in gastric adenocarcinoma1, but not in CRC2 and NSCLC3. This suggests that EGFR is an oncogenic driver for many ESCC individuals, and cetuximab could be an effective treatment option. We are currently using clinically applicable EGFR-IHC and -FISH to confirm this, enabling a companion diagnostics to guide treatment of ESCC if confirmed in the clinics. Our finding may represent the first report of the association of EGFR expression with cetuximab response in ESCC, and further prospective clinical investigation is warranted to support the expanding cetuximab indication into EGFR over-expressed ESCC. Further analysis of a cisplatin trial of the same cohort shows no activity correlation between cisplatin and cetuximab, suggesting the combination could be a good strategy for ESCC, or certuximab could be a good option for cisplatin resistant ESCC Conclusions: Cetuximab could be an effective treatment of ESCC.