FGFR2

  • Fibroblast growth factor receptor 2 (FGFR2)
  • Gene location: chromosome 10 (10q26)

FGFR2 Biology

  • The FGFR family of tyrosine kinase receptors includes FGFR1, FGFR2, FGFR3, and FGFR4.1,2
  • Upon growth factor binding, FGFRs dimerize and activate intracellular pathways crucial for cell proliferation, survival, and angiogenesis.1,3
  • The FGFR2 gene situated on chromosome 10 has over 25 isoforms derived from alternative splicing.3

Etiology and Epidemiology

  • In cholangiocarcinomas (CCAs), more than 150 FGFR2 fusion partners, notably BICC1, have been identified.4,5
  • These fusions, predominantly type 2, are mutually exclusive with FGFR2 mutations, and they often occur along with BAP1 alterations.6,7
  • FGFR aberrations are found in 7.1% of solid tumors, with FGFR2 being prevalent in CCA.8
  • FGFR2 fusions occur in 5% to 7% of all CCAs and in 10% to 20% of intrahepatic CCAs (iCCAs), and they are influenced by geographical and etiological factors.1,9
  • Some studies suggest a favorable prognosis associated with FGFR2 fusions, with longer overall survival (OS) and progression-free survival (PFS) noted in patients harboring these alterations and particularly in younger individuals.7,10-12

Testing for FGFR2

When to Test:

  • Patients with unresectable or metastatic biliary tract cancers (BTCs) who are candidates for systemic therapy should receive comprehensive molecular profiling at diagnosis.9

Available Testing Methods:

  • Next-generation sequencing (NGS) assays and break apart fluorescence in situ hybridization (FISH) assays are commonly used to identify patients with FGFR2 fusions/rearrangements.1,9,13
  • Some fusion breakpoints can be detected using cell free DNA assays, but associated sensitivity is lower than for tumor tissue testing. Therefore, comprehensive NGS-based tissue testing remains preferred to optimize the identification of targetable aberrations.

Guideline Testing Recommendations:

  • Testing for FGFR fusions or rearrangements is recommended in patients with unresectable or metastatic intrahepatic CCAs and extrahepatic CCAs due to the high associated incidence, but it may also be considered for unresectable or metastatic gallbladder cancer.

FGFR2-Targeted Therapy

Approved Agents:

  • The FDA has approved 2 targeted therapies for BTCs with FGFR2 fusions or rearrangements.14,15
  • Pemigatinib received accelerated approval in 2020 for use in patients with unresectable, locally advanced or metastatic CCA with FGFR2 fusions or rearrangements based on findings from the FIGHT-202 study (NCT02924376).16 The FoundationOne CDx assay was also approved as a companion diagnostic for pemigatinib.
  • Subsequently, in 2022, futibatinib received accelerated approval for previously treated, unresectable, locally advanced or metastatic, intrahepatic CCA harboring FGFR2 fusions or rearrangements based on findings from the TAS-120-101 trial (NCT02052778).17 Another FGFR inhibitor, infigratinib, received accelerated approval in 2021; it was withdrawn from the US market in 2023.18

Mechanism of Action:

  • Pemigatinib and futibatinib are small molecule kinase inhibitors targeting FGFR 1, 2, 3, and 4.14,15
  • These inhibitors covalently bind to FGFR, disrupting constitutive FGFR signaling, which plays a role in the proliferation and survival of malignant cells.14,15
  • By inhibiting FGFR phosphorylation and downstream signaling pathways, pemigatinib and futibatinib reduce cell viability in cancer cell lines that exhibit FGFR alterations, including FGFR fusions/rearrangements, amplifications, and mutations.14,15

Learn more about Futibatinib >

Learn more about Pemigatinib >

References

  1. Angerilli V, Fornaro L, Pepe F, et al. FGFR2 testing in cholangiocarcinoma: translating molecular studies into clinical practice. Pathologica. 2023;115(2):71-82. doi:10.32074/1591-951X-859
  2. Katoh M. Fibroblast growth factor receptors as treatment targets in clinical oncology. Nat Rev Clin Oncol. 2019;16(2):105-122. doi:10.1038/s41571-018-0115-y
  3. Neumann O, Burn TC, Allgäuer M, et al. Genomic architecture of FGFR2 fusions in cholangiocarcinoma and its implication for molecular testing. Br J Cancer. 2022;127(8):1540-1549. doi:10.1038/s41416-022-01908-1
  4. Arai Y, Totoki Y, Hosoda F, et al. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology. 2014;59(4):1427-34. doi:10.1002/hep.26890
  5. Wu YM, Su F, Kalyana-Sundaram S, et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 2013;3(6):636-647. doi:10.1158/2159-8290.CD-13-0050
  6. Chen L, Zhang Y, Yin L, et al. Fibroblast growth factor receptor fusions in cancer: opportunities and challenges. J Exp Clin Cancer Res. 2021;40(1):345. doi:10.1186/s13046-021-02156-6
  7. Jain A, Borad MJ, Kelley RK, et al. Cholangiocarcinoma with FGFR genetic aberrations: a unique clinical phenotype. JCO Precis Oncol. 2018;2:1-12. doi:10.1200/PO.17.00080
  8. Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res. 2016;22(1):259-267. doi:10.1158/1078-0432.CCR-14-3212
  9. NCCN. Clinical Practice Guidelines in Oncology. Biliary tract cancers, version 1.2024. Accessed April 10, 2024. https://www.nccn.org/professionals/physician_gls/pdf/btc.pdf
  10. Graham RP, Barr Fritcher EG, Pestova E, et al. Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Hum Pathol. 2014;45(8):1630-1638. doi:10.1016/j.humpath.2014.03.014
  11. Rizzato M, Brignola S, Munari G, et al. Prognostic impact of FGFR2/3 alterations in patients with biliary tract cancers receiving systemic chemotherapy: the BITCOIN study. Eur J Cancer. 2022;166:165-175. doi:10.1016/j.ejca.2022.02.013
  12. Abou-Alfa GK, Bibeau K, Schultz N, et al. Effect of FGFR2 alterations on overall and progression-free survival in patients receiving systemic therapy for intrahepatic cholangiocarcinoma. Target Oncol. 2022;17(5):517-527. doi:10.1007/s11523-022-00906
  13. Gonzoles-Medina A, Verdaguer H, Vila-Casadesus M, et al. FGFR fusion detection in plasma: A new era in the clinical monitoring of iCCA. J Clin Oncol. 2022;40(supp 16):4085. doi:10.1200/JCO.2022.40.16_suppl.40
  14. PEMAZYRE (pemigatinib). Prescribing information. Incyte; 2023. Accessed April 10, 2024. https://www.pemazyre.com/pemazyre-prescribing-information
  15. LYTGOBI (futibatinib). Prescribing information. Taiho Oncology; 2023. Accessed April 10, 2024. https://taihocorp-media-release.s3.us-west-2.amazonaws.com/documents/LYTGOBI_Prescribing_Information.pdf
  16. FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement of fusion. FDA. April 20, 2020. Accessed April 10, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pemigatinib-cholangiocarcinoma-fgfr2-rearrangement-or-fusion
  17. FDA grants accelerated approval to futibatinib for cholangiocarcinoma. FDA. September 30, 2022. Accessed April 10, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-futibatinib-cholangiocarcinoma
  18. Helsinn to withdraw NDA for cholangiocarcinoma. Press release. FDAnews. October 14, 2022. Assessed April 10, 2024. https://www.fdanews.com/articles/209797-helsinn-to-withdraw-nda-for-cholangiocarcinoma

Additional Reading

Angerilli V, Fornaro L, Pepe F, et al. FGFR2 testing in cholangiocarcinoma: translating molecular studies into clinical practice. Pathologica. 2023;115(2):71-82. doi:10.32074/1591-951X-859

Maruki Y, Morizane C, Arai Y, et al. Molecular detection and clinicopathological characteristics of advanced/recurrent biliary tract carcinomas harboring the FGFR2 rearrangements: a prospective observational study (PRELUDE Study). J Gastroenterol. 2021;56(3):250-260. doi:10.1007/s00535-020-01735-2

Uson Junior PLS, Borad MJ. Targeting fibroblast growth factor receptor pathway: Precision medicine for biliary cancer and beyond. Semin Liver Dis. 2023;43(2):218-225. doi:10.1055/a-2049-3149

Vogel A, Segatto O, Stenzinger A, Saborowski A. FGFR2 inhibition in cholangiocarcinoma. Annu Rev Med. 2023;74:293-306. doi:10.1146/annurev-med-042921-024707

Zugman M, Botrus G, Pestana RC, Uson Junior PLS. Precision medicine targeting FGFR2 genomic alterations in advanced cholangiocarcinoma: current state and future perspectives. Front Oncol. 2022;12:860453. doi:10.3389/fonc.2022.860453