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  • Review Article
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FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions

Nature Reviews Clinical Oncology volume 21, pages 312–329 (2024)Cite this article

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Abstract

Fibroblast growth factor (FGF) signalling via FGF receptors (FGFR1–4) orchestrates fetal development and contributes to tissue and whole-body homeostasis, but can also promote tumorigenesis. Various agents, including pan-FGFR inhibitors (erdafitinib and futibatinib), FGFR1/2/3 inhibitors (infigratinib and pemigatinib), as well as a range of more-specific agents, have been developed and several have entered clinical use. Erdafitinib is approved for patients with urothelial carcinoma harbouring FGFR2/3 alterations, and futibatinib and pemigatinib are approved for patients with cholangiocarcinoma harbouring FGFR2 fusions and/or rearrangements. Clinical benefit from these agents is in part limited by hyperphosphataemia owing to off-target inhibition of FGFR1 as well as the emergence of resistance mutations in FGFR genes, activation of bypass signalling pathways, concurrent TP53 alterations and possibly epithelial–mesenchymal transition-related isoform switching. The next generation of small-molecule inhibitors, such as lirafugratinib and LOXO-435, and the FGFR2-specific antibody bemarituzumab are expected to have a reduced risk of hyperphosphataemia and the ability to overcome certain resistance mutations. In this Review, we describe the development and current clinical role of FGFR inhibitors and provide perspective on future research directions including expansion of the therapeutic indications for use of FGFR inhibitors, combination of these agents with immune-checkpoint inhibitors and the application of novel technologies, such as artificial intelligence.

Key points

  • Several small-molecule pan-fibroblast growth factor receptor (FGFR) inhibitors (such as erdafitinib and futibatinib) and FGFR1–3 inhibitors (such as pemigatinib and infigratinib) have been approved for the treatment of patients with various cancers that harbour FGFR alterations detected using their companion diagnostics.

  • Objective response rates of patients with solid tumours receiving approved FGFR inhibitors are ~20–40%, whereas patients with FGFR1-rearranged myeloid or lymphoid neoplasms receiving pemigatinib have a complete response rate of 77%.

  • Gatekeeper, molecular-brake and other secondary FGFR alterations, activation of bypass signalling and TP53 alterations can all lead to resistance to FGFR inhibitors, and hyperphosphataemia owing to off-tumour inhibition of FGFR1 can lead to dose reduction or treatment discontinuation.

  • Prospective data indicate that the activity of selective FGFR2 or FGFR3 inhibitors is unaffected by gatekeeper mutations and that these agents are less likely to induce hyperphosphataemia; these more-selective agents are expected to form the third generation of FGFR inhibitors for patients with FGFR2/3-altered cancers.

  • The anti-FGFR2b antibody bemarituzumab is currently being tested in combination with chemotherapy in phase III trials in patients with gastric or gastro-oesophageal junction adenocarcinoma harbouring FGFR2 amplifications and/or overexpression.

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Fig. 1: Overview of FGFR signalling and mechanisms of oncogenic activation.
Fig. 2: FGFR inhibitors and drug-binding pockets.
Fig. 3: Epithelial–mesenchymal plasticity and resistance to FGFR2 isoform-specific therapeutic antibodies.

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Acknowledgements

This work was partly supported by grants-in-aid from Masaru Katoh’s Fund for Knowledge-Base and Global Network Projects (Masuko Katoh and Masaru Katoh) and Fondazione Donato-Venturi (G.B.).

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Authors and Affiliations

  1. M & M Precision Medicine, Tokyo, Japan

    Masuko Katoh & Masaru Katoh

  2. Drug Development Department (DITEP), Institut Gustave Roussy, Université Paris-Saclay, Villejuif, France

    Yohann Loriot

  3. INSERM U981, Institut Gustave Roussy, Université Paris-Saclay, Villejuif, France

    Yohann Loriot

  4. Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy

    Giovanni Brandi & Simona Tavolari

  5. Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy

    Giovanni Brandi

  6. Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Zev A. Wainberg

  7. Department of Omics Network, National Cancer Center, Tokyo, Japan

    Masaru Katoh

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Contributions

Masuko Katoh and Masaru Katoh researched data for the manuscript, made substantial contributions to discussions of content, and wrote the manuscript. All authors reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Masaru Katoh.

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Competing interests

Y.L. has acted as a consultant and/or adviser for Astellas, AstraZeneca, Bristol Myers Squibb, Gilead, Janssen, Merck KGaA, Pfizer, Roche, Seattle Genetics and Taiho and has received research grants from Celsius, Janssen and Sanofi. G.B. has acted as an adviser for Incyte, Lilly and Taiho and has received research grants from Incyte and Ipsen. Z.A.W. has been a consultant for Amgen, Arcus, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Gilead, Ipsen, Merck, Novartis and Seagen, has received research grants from Arcus, Bristol Myers Squibb and Plexxikon, and has served on the data and safety monitoring boards of Compass, Daiichi Sankyo, Mirati and Pfizer.

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Nature Reviews Clinical Oncology thanks J. Garcia-Donas who co-reviewed with T. Grazioso, Jacek Otlewski who co-reviewed with Malgorzata Zakrzewska, Sumanta Pal, Roberto Ronca and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Katoh, M., Loriot, Y., Brandi, G. et al. FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions. Nat Rev Clin Oncol 21, 312–329 (2024). https://doi.org/10.1038/s41571-024-00869-z

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