Abstract 1097: FGFR2 in-frame indels: A novel targetable alteration in intrahepatic cholangiocarcinoma
Authors: Yvonne Y. Li, James M. Cleary, Srivatsan Raghavan, Liam F. Spurr, Qibiao Wu, Lei Shi, Lauren K. Brais, Maureen Loftus, Lipika Goyal, Anuj K. Patel, Atul B. Shinagare, Thomas E. Clancy, Geoffrey Shapiro, Ethan Cerami, William R. Sellers, William C. Hahn, Matthew Meyerson, Nabeel Bardeesy, Andrew D. Cherniack, Brian M. Wolpin
Journal: Cancer Research (2020)

Abstract Biliary cancers include intrahepatic cholangiocarcinoma (IHCC), extrahepatic cholangiocarcinoma (EHCC), and gallbladder cancer (GBC). These cancers are clinically, pathologically, and biologically heterogeneous, but are all aggressive with poor prognosis and few available therapies. Potentially actionable genomic alterations described to date include IDH1 mutations, FGFR2 fusions, BRAF V600E mutations, HER2 amplification/mutation, and BRCA1/2 mutations. FGFR inhibitors have demonstrated encouraging efficacy in patients with FGFR2 oncogenic fusions; however, the efficacy of these inhibitors in patients with other types of FGFR alterations is less clear. We analyzed somatic alterations in 272 patients with biliary cancers (135 IHCCs, 34 EHCCs, and 59 GBCs) that underwent targeted OncoPanel sequencing at Dana-Farber Cancer Institute. The identified oncogenic alterations were similar to those previously reported in cholangiocarcinoma genomic landscapes. Mutational signature analyses found genomic features of microsatellite instability in 5 cases, APOBEC in 4 cases, and homologous recombination repair deficiency in 7 cases. Clinicopathological and outcome data for these patients are being collected to evaluate for associations with genomic findings. 16 FGFR2 translocations involving intron 17 were identified in the IHCC cohort (14% of evaluable IHCCs). Surprisingly, 5 IHCCs (4% of evaluable cases) harbored extracellular domain FGFR2 indels, of which p.W290_I291delinsC was previously reported to show oncogenic activity in vitro. Two cases harbored an identical FGFR2 p.H167_N173del. In vitro expression of this deletion resulted in oncogenic transformation, and that this growth could be inhibited by FGFR inhibitors. The two patients with FGFR2 p.H167_N173del were treated with an FGFR-1/2/3 inhibitor (Debio-1347), and both achieved durable partial response (PR) of over 11 months. We followed the first patient with tumor sequencing at five timepoints during her care and found that at resistance to Debio-1347, she developed an FGFR2 kinase domain mutation (p.L617F) that was subsequently demonstrated to confer resistance to Debio-1347 in vitro. This patient was then treated with a second FGFR inhibitor and experienced a PR lasting 17 months. At resistance to this second FGFR inhibitor, the tumor was biopsied and found to harbor a previously undetected BRAF p.L597Q mutation. The second patient remains on active treatment. Our data show that extracellular domain FGFR2 in-frame indels are rare but targetable novel oncogenic alterations in IHCC. An expanded search of AACR Project GENIE data found 18 extracellular FGFR2 in-frame indels in diverse tumor types, supporting further functional evaluation and clinical targeting of these indels across tumor types. Citation Format: Yvonne Y. Li, James M. Cleary, Srivatsan Raghavan, Liam F. Spurr, Qibiao Wu, Lei Shi, Lauren K. Brais, Maureen Loftus, Lipika Goyal, Anuj K. Patel, Atul B. Shinagare, Thomas E. Clancy, Geoffrey Shapiro, Ethan Cerami, William R. Sellers, William C. Hahn, Matthew Meyerson, Nabeel Bardeesy, Andrew D. Cherniack, Brian M. Wolpin. FGFR2 in-frame indels: A novel targetable alteration in intrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1097.