FGFR3 and FGFR2

  • FGFR3 (fibroblast growth factor receptor 3) and FGFR2 (fibroblast growth factor receptor 2) encode receptor tyrosine kinases of the FGFR family (FGFR1 to FGFR4).1,2
  • Gene Location: Chromosome 4 (4p16.3) for FGFR3; chromosome 10 (10q26.13) for FGFR2.1

Biology

  • Each FGFR has 3 extracellular immunoglobulin-like domains, a transmembrane domain, and an intracellular kinase domain. Binding of 1 of 22 FGF ligands causes dimerization and activation of RAS-MAPK, PI3K-AKT, PLCγ, and STAT signaling, which regulate proliferation, differentiation, survival, and angiogenesis.2,3
  • Activating FGFR3 mutations: R248C, S249C, G370C, and Y373C create cysteine residues that form disulfide bonds between receptors, causing ligand-independent dimerization and constitutive signaling. S249C is the most common, accounting for up to about 70% of FGFR3 mutations.3
  • FGFR3 fusions: FGFR3-TACC3 and FGFR3-BAIAP2L1 join the FGFR3 kinase to partner domains that drive oligomerization and activation.3
  • FGFR3-altered tumors are enriched in the luminal-papillary subtype of muscle-invasive bladder cancer (MIBC), which has lower immune infiltration.5,6

Etiology and Epidemiology

  • Locally advanced or metastatic urothelial carcinoma (la/mUC): approximately 20% of tumors have FGFR3 alterations; about 80% of these are point mutations, FGFR3 fusions are less common, and FGFR2 alterations are rare.7
  • By stage: FGFR3 mutations occur in around 70% of non-muscle-invasive bladder cancers (NMIBC) and about 15% of MIBC.3
  • Upper tract urothelial carcinoma (UTUC): about 40% harbor FGFR3 alterations; in one series, FGFR3 was altered in 35.6% of high-grade UTUC vs 21.6% of high-grade bladder tumors.7,8
  • Across cancers: FGFR aberrations were found in 7.1% of 4853 solid tumors sequenced by NGS, with urothelial carcinoma among the most frequently altered tumor types.4
  • In the TCGA MIBC cohort, luminal-papillary tumors (35% of 408 MIBC) carried most FGFR3 mutations, amplifications, and FGFR3-TACC3 fusions.5

Testing

When to Test:

  • Patients with la/mUC should undergo FGFR3 testing at diagnosis of advanced disease so results are available when second-line therapy is chosen.6,9

Testing Methodologies:

  • Real-time RT-PCR: the QIAGEN therascreen FGFR RGQ RT-PCR Kit (FFPE tumor tissue) is the FDA-approved companion diagnostic for erdafitinib. It detects FGFR3 R248C, S249C, G370C, and Y373C mutations and FGFR3-TACC3 fusions (variants 1 and 3); turnaround is about 3 to 5 days.6,10
  • Next-generation sequencing (NGS): detects mutations, fusions, and copy-number changes in one assay (about 5 to 21 days); RNA-based sequencing is preferred for fusions. In THOR cohort 1, 25% of patients were identified by local NGS.6,7
  • Specimen: archival FFPE tissue from the diagnostic sample (TURBT or upper tract) is generally appropriate. ctDNA is less accurate for fusions, and urine-based testing remains investigational.6

Guideline Recommendations

  • Expert consensus (2026): test all patients with la/mUC for FGFR3 at diagnosis with a validated qPCR or NGS assay.9
  • NCCN (Bladder Cancer, V.2.2026): recommends molecular testing in advanced disease, including FGFR3 alterations, to guide erdafitinib eligibility.11

Targeted Therapy

Approved Agents

Erdafitinib (Balversa)

FDA-Approved Indication:

  • Adults with la/mUC with susceptible FGFR3 genetic alterations whose disease has progressed on or after at least 1 prior line of systemic therapy. Not recommended for patients eligible for, but not yet treated with, PD-1 or PD-L1 inhibitor therapy.10

Mechanism of Action:

  • Oral, reversible, ATP-competitive inhibitor of FGFR1 to FGFR4 kinase activity. Serum phosphate rises with on-target FGFR inhibition and is used to guide dose uptitration.10

Drug Information: Learn more about Erdafitinib ›

Patient Resources: https://www.balversa.com/

Investigational Agents

  • TAR-210 (intravesical erdafitinib releasing system): investigational in NMIBC with susceptible FGFR alterations identified by urine or TURBT tissue testing; phase 3 MoonRISe-1 (NCT06319820) and MoonRISe-3 (NCT06919965) are enrolling.12

References

  1. NCBI Gene. FGFR3 (Gene ID 2261) and FGFR2 (Gene ID 2263) [Homo sapiens]. Accessed October 2026.
  2. Du S, Zhang Y, Xu J. Current progress in cancer treatment by targeting FGFR signaling. Cancer Biol Med. 2023;20(7):490-499. doi:10.20892/j.issn.2095-3941.2023.0137
  3. Bogale DE. The roles of FGFR3 and c-MYC in urothelial bladder cancer. Discov Oncol. 2024;15(1):295. doi:10.1007/s12672-024-01173-z
  4. Helsten T, Elkin S, Arthur E, et al. 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
  5. Robertson AG, et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell. 2017;171(3):540-556.e25. doi:10.1016/j.cell.2017.09.007
  6. Mansinho A, et al. FGFR testing in metastatic urothelial carcinoma: who, when, and how to test. Cancers (Basel). 2026;18(3):444. doi:10.3390/cancers18030444
  7. Maguire WF, Chang E, Mulkey F, et al. FDA approval summary: erdafitinib for FGFR3-altered locally advanced or metastatic urothelial carcinoma. Clin Cancer Res. Published online August 12, 2026. doi:10.1158/1078-0432.CCR-26-1154
  8. Sfakianos JP, et al. Genomic characterization of upper tract urothelial carcinoma. Eur Urol. 2015;68(6):970-977. doi:10.1016/j.eururo.2015.07.039
  9. Compérat EM, et al. FGFR3 testing in urothelial carcinoma: an expert commentary on best practices from patient identification to result reporting. Eur Urol Oncol. 2026;9(4):977-985. doi:10.1016/j.euo.2026.06.003
  10. Balversa (erdafitinib) tablets. Prescribing information. Janssen Products, LP; revised 10/2025. Accessed October 2026.
  11. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Bladder Cancer V.2.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed October 2026. To view the most recent and complete version of the guideline, go online to NCCN.org.
  12. ClinicalTrials.gov. MoonRISe-1 (NCT06319820) and MoonRISe-3 (NCT06919965). Accessed October 2026.