Abstract 4114: Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in FGFR2 fusion-positive cholangiocarcinoma patients

Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in a broad range of cancers and occur in ~20% of ICCs. As seen with other targeted therapies, however, acquired resistance has limited the efficacy of selective FGFR kinase inhibitors such as BGJ398. In a phase II trial of patients with advanced refractory cholangiocarcinoma harboring an FGFR gene alteration, BGJ398 displayed an overall response rate of 22%, but the durability of response was short in some patients. We report the molecular basis of acquired resistance in 4 patients with advanced FGFR2-fusion positive ICC via integrative genomic characterization of cell-free circulating tumor DNA (cfDNA), the primary tumor, and metastases. Each patient enjoyed an initial response, but all subsequently progressed within 10 months. Serial analysis of cfDNA revealed multiple point mutations in the FGFR2 kinase domain at progression (Table 1). The gatekeeper mutation, p. V564F, sterically hinders drug binding and was identified in 3 of 4 patients. In patient #1, five different FGFR2 mutations were detected in the post-progression cfDNA but only one, p. K641R, was identified in the post-progression biopsy. A rapid autopsy was performed, and genomic characterization of 12 metastatic lesions revealed marked inter- and intra-lesional heterogeneity, with different FGFR2 mutations in individual resistant clones. Molecular modeling and in vitro studies indicated that each mutation lead to BGJ398 resistance that was surmountable by structurally distinct FGFR inhibitors. Thus, our report provides the first genetic evidence of clinical acquired resistance to FGFR inhibitor therapy in patients and informs future strategies for detecting mechanisms of resistance and promoting more durable remissions. Note: This abstract was not presented at the meeting. Citation Format: Lipika Goyal, Supriya K. Saha, Leah Y. Liu, Giulia Siravegna, Ignaty Leshchiner, Leanne G. Ahronian, Jochen K. Lennerz, Phuong Vu, Benedetta Mussolin, Stephanie Reyes, Pascal Furet, A. John Iafrate, Gad Getz, Diana G. Porta, Ralph Tiedt, Alberto Bardelli, Dejan Juric, Ryan B. Corcoran, Nabeel Bardeesy, Andrew X. Zhu. Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in FGFR2 fusion-positive cholangiocarcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4114. doi:10.1158/1538-7445.AM2017-4114