Abstract 5446: FPA144: A therapeutic antibody for treating patients with gastric cancers bearing FGFR2 gene amplification

Abstract

Abstract A subset of patients with gastric cancer have an amplification of the receptor tyrosine kinase fibroblast growth factor receptor 2 (FGFR2) gene. The amplification is most common in the diffuse type of gastric cancer and its presence correlates with poor patient prognosis. Although it has been reported that there is high expression of FGFR2 protein in patients with the amplification, it has been unknown which of the two major FGFR2 isoforms, FGFR2b or 2c, is expressed. In this study, we demonstrate, by both qPCR and immunohistochemistry using FGFR2b-selective antibodies, that it is the FGFR2b isoform, and not FGFR2c, that is overexpressed in gastric cancer tumors that contain the FGFR2 amplification. Five Prime Therapeutics has developed an FGFR2b-specific antibody, FPA144, to treat patients with gastric cancers bearing amplification of the FGFR2 gene. FPA144 is glycoengineered for enhanced antibody-dependent cell cytotoxicity (ADCC). FPA144 causes tumor growth inhibition by 72% to 100% in gastric cancer xenograft models with FGFR2 gene amplification that overexpress the FGFR2b protein isoform. In the SNU-16 model, FPA144 reduces the levels of FGFR2b protein expressed in the tumors by approximately 50%, and decreases both FGFR2b phosphorylation and phosphorylation of the downstream effector, FRS2. The anti-tumor effect of FPA144 is additive with the standard of care chemotherapy regimens of 5-fluoruracil/cisplatin and paclitaxel in the OCUM-2 gastric cancer xenograft model. Since FPA144, unlike small molecule FGFR tyrosine kinase inhibitors, blocks signaling by only the FGFR2b and not the other FGFRs, we expect a favorable toxicology profile, either alone or in combination with chemotherapy. In addition, by engaging immune effector cells for direct tumor cell killing, FPA144 has a second mechanism of action that small molecule FGFR tyrosine kinase inhibitors do not have. We anticipate starting clinical trials of FPA144 in the last quarter of 2014. Citation Format: Abigael T. Gemo, Amit M. Deshpande, Servando Palencia, David I. Bellovin, Thomas J. Brennan, Namrata S. Patil, Carol Huang, Gerrit Los, Kristen L. Pierce. FPA144: A therapeutic antibody for treating patients with gastric cancers bearing FGFR2 gene amplification. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5446. doi:10.1158/1538-7445.AM2014-5446