Therapeutic Targeting of Extracellular FGFR2 Activating Deletions in Intrahepatic CCA

2020 Year in Review - Cholangiocarcinoma —December 20, 2020

Extracellular domain FGFR2 in-frame deletions might be a novel genomic alteration in intrahepatic CCA with potential clinical sensitivity to FGFR inhibitors.

The activity of FGFR inhibitors in patients with CCA harboring FGFR2 fusions is well-documented; however, there is less clarity on the efficacy of FGFR inhibitors in patients with other FGFR2 activating genetic alterations. At the ASCO 2020 Gastrointestinal Cancers Symposium, the identification of a novel FGFR2 genomic alteration, namely extracellular domain FGFR2 in-frame deletions, and the oncogenic activity of FGFR inhibitors in vitro and in vivo in patients with CCA harboring this alteration were reported.

In this study, genomic alterations were assessed using the OncoPanel targeted NGS in patients with CCA before and after treatment with FGFR inhibitors in select patients. A total of 284 patients with biliary tract cancers, including 139 patients with intrahepatic CCA, underwent sequencing; the median age of the study population was 64 years (range, 20-89 years). In patients with intrahepatic CCA, genomic sequencing found IDH1 mutations in 26 patients (19%), FGFR2 fusions in 19 patients (14%), IDH2 mutations in 6 patients (4%), extracellular domain FGFR2 deletion in 5 (3.5%), BRAF V600E mutation in 4 (2.9%), and BRCA1/2 in 3 (2.2%). Of the extracellular domain FGFR2 deletions identified in intrahepatic CCA, 2 patients harbored an exon 5 deletion, FGFR2 p.H167_N173del.

Preclinical studies demonstrated the oncogenic activity of the FGFR2 p.H167_N173del extracellular domain in-frame FGFR2 deletion in in vitro and in vivo tests. In soft agar colony formation assays, the expression of the novel FGFR2 p.H167_N173del in 3T3 cells resulted in oncogenic transformation. In xenograft mouse models, 3T3 cells expressing FGFR2 p.H167_N173del formed tumors as subcutaneous xenografts.

In the clinical setting, there is preliminary evidence to suggest potential activity of FGFR2 inhibitors in patients with extracellular domain in-frame FGFR2 deletion. Two patients with metastatic intrahepatic CCA harboring FGFR2 p.H167_N173del were treated with Debio1347, an oral FGFR1-3 inhibitor. The first patient was a 65-year-old man who achieved a partial response and had been treated with the drug for 14 months. The second patient was a 48-year-old woman who achieved a partial response for 13 months and developed acquired resistance with a secondary mutation (FGFR2 p. L617F) in the kinase domain. She was subsequently treated with another FGFR inhibitor and achieved a partial response for 17 months. Following disease progression, additional genetic alterations were identified, including FGFR2 N549K and NRAS Q61K mutations.

Based on these results, extracellular domain FGFR2 in-frame deletions are a novel genomic alteration in intrahepatic CCA that may show clinical sensitivity to FGFR inhibitors, warranting further clinical testing.

Source: Cleary JM, et al. J Clin Oncol. 2020;38(suppl_4). Abstract 567.

Last modified: March 11, 2021

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