FGFR2b

  • Fibroblast Growth Receptor Factor 2b (FGFR2b)
  • Gene Location: chromosome 10 (10p26)

Biology

  • The family of fibroblast growth factor receptors (FGFRs) consists of four receptor tyrosine kinases (RTKs): FGFR1 to FGFR4. These cell surface proteins possess 3 immunoglobulin (Ig)-like extracellular domains, a single-pass transmembrane domain, and an intracellular tyrosine kinase domain.1
  • The ligands for FGFRs are Fibroblast Growth Factors (FGFs), a family of 22 small proteins with diverse expression patterns.1
  • The binding of FGFs drives the dimerization of FGFRs triggering downstream signaling pathways, including PI3K, ATK, MAPK, STAT, and PLC, which regulate various cell processes such as proliferation, differentiation, cell migration and survival.2-5
  • FGFR2b (also known as fibroblast growth factor receptor 2 isoform IIIb) is one of the proteins resulting from the transcription and subsequent translation of the alternatively spliced FGFR2 gene.1-4
  • The FGFR2b protein receptor is primarily localized on epithelial cell membranes.5 
  • Due to the FGFR2b unique extracellular domain, only a specific subset of FGF ligands will bind to the receptor – FGF ligands 7, 10, and 22 specifically bind to FGFR2b.1-2
  • Aberrant activation of FGFR2b can drive the transformation and proliferation of tumor cells as well as angiogenesis.1-4

Etiology and Epidemiology

  • FGFR2b protein overexpression is an emerging biomarker prevalent in ~38% of patients with advanced G/GEJC with 2+ or 3+ staining in any percentage of tumor cells (any %, 2+/3+ TC–positive) and in ~17% with 2+ or 3+ staining in ≥10% of tumor cells (≥10%, 2+/3+ TC positive).5
  • FGFR2b protein overexpression in gastric cancer may be associated with poorly differentiated diffuse-type histology and poor outcomes, including lower overall survival, and warrants further investigation.1-7
  • FGFR2 gene amplification is observed in approximately 3% to 9% of GC cases.5
  • FGFR2b protein overexpression can be independent of FGFR2 gene amplification in advanced G/GEJC and further studies are warranted to definitively demonstrate a correlation.8

FGFR2b Testing

When to Test:

  • Biomarker testing should be performed at diagnosis for patients with newly diagnosed, locally advanced, unresectable, or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma to evaluate for currently targetable biomarkers.9
  • Current guidelines do not include specific recommendations for FGFR2b testing, as no agents targeting the protein FGFR2b are FDA approved as of March 2025.9

Available Testing Methods:

  • FGFR2 genomic alterations can be detected using next-generation sequencing (NGS), fluorescence in-situ hybridization (FISH), or immunohistochemistry (IHC), although NGS and FISH are less favored to establish FGFR2b protein overexpression due to the lack of definitive concordance data between FGFR2 gene amplification and FGFR2b protein overexpression.6
  • IHC is the preferred method for identifying FGFR2b protein overexpression, offering lower cost, faster turnaround.2,4
  • Since FGFR2b protein overexpression can occur in the absence of FGFR2 gene amplification, IHC detection of FGFR2b protein overexpression remains the appropriate testing methodology.2,4

Guideline Recommendations for Testing:

  • Current guidelines do not have recommendations regarding FGFR2b testing as of March 2025.9
  • For currently actionable biomarkers, IHC/ISH/targeted PCR are the preferred approaches to assess biomarkers initially for patients with G/GEJC. However, NGS testing through a CLIA-approved laboratory may be considered later in the clinical course of patients who have sufficient tumor tissue available for testing.9
Figure

FGFR2b Targeted Therapy

Approved Agents:

  • There are currently no FDA-approved agents that target the protein FGFR2b within the setting of G/GEJC.6,11-13

Investigational Agents:

  • Bemarituzumab is a first-in-class humanized IgG1 monoclonal antibody that selectively binds to the cell surface protein receptor FGFR2b and is presently under investigation for the treatment of FGFR2b-positive/HER-negative previously untreated advanced GC and gastroesophageal junction cancer.6,11-13

Mechanism of Action:

  • Bemarituzumab’s mechanism of action is twofold: (1) it directly inhibits FGFR2b ligand binding and downstream signaling, and (2) it enhances antibody-dependent cell-mediated cytotoxicity (ADCC).1

Investigational Studies:

  • FIGHT10
    • ClinicalTrials.gov: NCT03694522
    • Study design: A phase 1/2, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of bemarituzumab-mFOLFOX6 in patients with advanced HER-2 non-positive gastric cancer prescreened for FGFR2b overexpression (via IHC) and/or FGFR2 gene amplification (via circulating tumor DNA [ctDNA] assay).10
  • FORTITUDE-10111,12
    • ClinicalTrials.gov: NCT05052801
    • Study design: A double-blind, placebo-controlled phase 3 study in patients with untreated, unresectable locally advanced or metastatic gastric or GEJ adenocarcinoma not amenable to curative therapy.
  • FORTITUDE-10213,14
    • ClinicalTrials.gov: NCT05111626
    • Study design: A phase 1b/3 study in patients (pts) with unresectable locally advanced or metastatic gastric or GEJ adenocarcinoma not amenable to curative therapy. Part 1 is an open-label safety lead-in; Part 2 is a double-blind, placebo-controlled study to evaluate efficacy and safety.

References

  1. Xiang H, Chan AG, Ahene A, et al. Preclinical characterization of bemarituzumab, an anti-FGFR2b antibody for the treatment of cancer. MAbs. 13(1):1981202. doi:10.1080/19420862.2021.1981202
  2. Sato Y, Okamoto K, Kawano Y, et al. Novel biomarkers of gastric cancer: current research and future perspectives. J Clin Med. 2023;12(14):4646. doi:10.3390/jcm12144646
  3. Khosravi F, Ahmadvand N, Bellusci S, Sauer H. The multifunctional contribution of fgf signaling to cardiac development, homeostasis, disease and repair. Front Cell Dev Biol. 2021;9. doi:10.3389/fcell.2021.672935
  4. Ahn S, Lee J, Hong M, et al. FGFR2 in gastric cancer: protein overexpression predicts gene amplification and high H-index predicts poor survival. Mod Pathol. 2016;29(9):1095-1103. doi:10.1038/modpathol.2016.96
  5. Lian Y, Bodian D, Shehu A. Elucidating the role of wildtype and variant fgfr2 structural dynamics in (dys)function and disorder. Int J Mol Sci. 2024;25(8):4523. doi:10.3390/ijms25084523.
  6. Wainberg ZA, Kang YK, Lee KW, et al. Bemarituzumab as first-line treatment for locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma: final analysis of the randomized phase 2 FIGHT trial. Gastric Cancer. 2024 May;27(3):558-570. doi:10.1007/s10120-024-01466-w.
  7. Rha SY, Zhang Y, Elme A, et al. Prevalence of FGFR2b protein overexpression in advanced gastric cancers during prescreening for the phase III FORTITUDE-101 trial. JCO Precis Oncol. 2025;(9):e2400710. doi:10.1200/PO-24-00710
  8. Zhang J, Tang PMK, Zhou Y, et al. Targeting the oncogenic FGF-FGFR axis in gastric carcinogenesis. Cells. 2019;8(6):637. doi:10.3390/cells8060637.
  9. National Comprehensive Cancer Network. NCCN guidelines version 2.2025: gastric cancer. NCCN; 2025. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf
  10. Wainberg ZA, Enzinger PC, Kang YK, et al. Bemarituzumab in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma (FIGHT): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet Oncol. 2022;23(11):1430-1440. doi:10.1016/S1470-2045(22)00603-9
  11. Smyth EC, Chao J, Muro K, et al. Trial in progress: phase 3 study of bemarituzumab + mFOLFOX6 versus placebo + mFOLFOX6 in previously untreated advanced gastric or gastroesophageal junction (GEJ) cancer with FGFR2b overexpression (FORTITUDE-101). JCO. 2022;40(suppl 16):TPS4164-TPS4164. doi:10.1200/JCO.2022.40.16_suppl.TPS4164
  12. Bemarituzumab or placebo plus chemotherapy in gastric cancers with fibroblast growth factor receptor 2b (FGFR2b) overexpression (FORTITUDE-101). ClinicalTrials.gov. Updated February 7, 2025. Accessed April 8, 2025. https://clinicaltrials.gov/study/NCT05052801
  13. Bemarituzumab plus chemotherapy and nivolumab versus chemotherapy and nivolumab for FGFR2b overexpressed untreated advanced gastric and gastroesophageal junction cancer. (FORTITUDE-102). ClinicalTrials.gov. Updated November 22, 2024. Accessed April 8, 2025. https://clinicaltrials.gov/study/NCT05111626