SEARCHNARRATIVE_REVIEWoncology, molecular biology

narrative_review·oncology, molecular biology, clinical trial, pharmacology·PMC10815772

Molecular Targeting of the Fibroblast Growth Factor Receptor Pathway across Various Cancers

International Journal of Molecular Sciences · 6 authors, 1 centre

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This review summarizes the role of FGFR alterations in multiple cancers and the development of FGFR inhibitors. Approximately 7.1% of solid tumors harbor FGFR aberrations, and four FDA-approved inhibitors (pemigatinib, infigratinib, erdafitinib, futibatinib) have shown efficacy in cholangiocarcinoma, urothelial cancer, and myeloid/lymphoid neoplasms. The clinical significance lies in the potential for personalized medicine targeting FGFR alterations, though challenges remain with acquired resistance and toxicity management.

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**Background:** Fibroblast growth factor receptors (FGFRs) are receptor tyrosine kinases that regulate cellular proliferation, migration, survival, and angiogenesis. Dysregulation of FGFR signaling through gene amplifications, mutations, and fusions drives oncogenesis in approximately 7.1% of solid tumors (66% amplifications, 26% mutations, 8% rearrangements). This review covers the FGFR signaling pathway, FGFR alterations across cancers, FDA-approved inhibitors, resistance mechanisms, and future directions.

**Methods:** This is a narrative review synthesizing data from clinical trials, genomic profiling studies, and preclinical models. Key trials include FIGHT-202 (pemigatinib in cholangiocarcinoma), CBGJ398X2204 (infigratinib), BLC2001 (erdafitinib in urothelial cancer), FOENIX-CCA2 (futibatinib), and FIGHT-203 (pemigatinib in myeloid/lymphoid neoplasms). The review also discusses multi-kinase inhibitors, ligand traps, monoclonal antibodies, and antibody-drug conjugates.

**Key Results:** - Pemigatinib (FGFR1-3 inhibitor) showed ORR 35.5% (95% CI: 26.5–45.4) in FGFR2 fusion-positive cholangiocarcinoma (FIGHT-202), with median OS 17.5 months (95% CI: 14.4–22.9). In FIGHT-203, complete response rate was 64.7% in myeloid/lymphoid neoplasms with FGFR1 rearrangements. - Infigratinib (FGFR1-3) achieved ORR 23.1% (95% CI: 15.6–32.2) in cholangiocarcinoma, with median PFS 7.3 months. - Erdafitinib (FGFR1-4) in urothelial cancer (BLC2001) showed ORR 40% (95% CI: 31–50), median PFS 5.5 months, median OS 13.8 months. In the THOR trial, erdafitinib improved OS vs. chemotherapy (12.1 vs. 7.8 months; HR 0.64, 95% CI: 0.47–0.88, p=0.005). - Futibatinib (irreversible FGFR1-4) in cholangiocarcinoma (FOENIX-CCA2) achieved ORR 42% (95% CI: 32–52), median OS 21.7 months, median PFS 9.0 months. - Common adverse effects include hyperphosphatemia, stomatitis, diarrhea, fatigue, and ocular toxicities (e.g., central serous retinopathy in 27% of erdafitinib patients). - Resistance mechanisms include FGFR gatekeeper mutations (e.g., FGFR2 V564F), activation of alternative RTKs (e.g., EGFR, HER2), PI3K/AKT pathway upregulation, and epithelial-mesenchymal transition.

**Clinical Implications:** FGFR inhibitors provide a targeted therapy option for patients with FGFR-altered cancers, particularly cholangiocarcinoma, urothelial carcinoma, and myeloid/lymphoid neoplasms. Third-generation inhibitors like futibatinib can overcome some acquired resistance mutations. Combination strategies with chemotherapy, immunotherapy, or targeted agents (e.g., mTOR inhibitors, CDK4/6 inhibitors) are under investigation. Challenges include patient selection, tumor heterogeneity, management of toxicities (especially hyperphosphatemia and ocular effects), and acquired resistance. Ongoing trials are exploring novel agents (e.g., bemarituzumab, lirafugratinib) and combinations to improve outcomes.

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narrative_review

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oncology

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84% · B

ORIGINAL PAPER

PMC10815772

Molecular Targeting of the Fibroblast Growth Factor Receptor Pathway across Various Cancers

International Journal of Molecular Sciences

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ABSTRACT

Abstract Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that are involved in the regulation of cell proliferation, survival, and development. FGFR alterations including amplifications, fusions, rearrangements, and mutations can result in the downstream activation of tyrosine kinases, leading to tumor development. Targeting these FGFR alterations has shown to be effective in treating cholangiocarcinoma, urothelial carcinoma, and myeloid/lymphoid neoplasms, and there are currently four FGFR inhibitors approved by the Food and Drug Administration (FDA). There have been developments in multiple agents targeting the FGFR pathway, including selective FGFR inhibitors, ligand traps, monoclonal antibodies, and antibody–drug conjugates. However, most of these agents have variable and low responses, with some intolerable toxicities and acquired resistances. This review will summarize previous clinical experiences and current developments in agents targeting the FGFR pathway, and will also discuss future directions for FGFR-targeting agents. Keywords: FGF, FGFR, fibroblast growth factor receptor, fibroblast growth factor, targeted therapy, genomic profiling, personalized medicine

CITATION EXPORT

Khine S Shan, Shivani Dalal, Nyein Nyein Thaw Dar et al.. Molecular Targeting of the Fibroblast Growth Factor Receptor Pathway across Various Cancers. International Journal of Molecular Sciences. (2024). https://doi.org/10.3390/ijms25020849

AUTHORS

6 · 1 CENTRES

Khine S Shan, Shivani Dalal, Nyein Nyein Thaw Dar, Omani McLish, Matthew Salzberg, Brian A Pico

1Memorial Health Care, Division of Hematology and Oncology, Pembroke Pines, FL 33028, USA; [email protected] (S.D.); [email protected] (N.N.T.D.); [email protected] (O.M.); [email protected] (M.S.);