Selective FGFR/FGF pathway inhibitors: inhibition strategies, clinical activities, resistance mutations, and future directions

ABSTRACT

Introduction: Fibroblast growth factor receptor (FGFR)/fibroblast growth factor (FGF) is a pathway characterized by recurring alterations in cancer. Its dysregulations enhance cancer cell proliferation, survival, migration and invasion, as well as angiogenesis and immune evasion.

Areas covered: FGFR/FGF selective inhibitors belong to a broad class of drugs with some being approved for specific indications and others under investigation in ongoing phase I and II clinical trials. In this review, all available clinical data from trials on selective FGFR/FGF inhibitors as well as described resistance mutations and mechanisms are presented. FGFR/FGF pathway inhibitors are classified according to the mechanism they employ to dampen/suppress signaling and to the preferred FGFR binding mode when X-ray crystal structure is available.

Expert opinion: Data presented suggests the general actionability of FGFR1,2,3 mutations and fusions across histologies, whereas FGFR1,2,3 amplifications alone are poor predictors of response to tyrosine kinase inhibitors. Overexpression on immunohistochemistry (IHC) of FGF19, the stimulatory ligand of FGFR4, can predict response to FGFR selective inhibitors in hepatocellular carcinoma. Whereas IHC overexpression of FGFR1,2,3 is not sufficient to predict benefit from FGFR inhibitors across solid tumors. FGFR1,2,3 mRNA overexpression can predict response even in absence of structural alteration. Data on resistance mutations suggests the need for new inhibitors to overcome gatekeeper mutations.

KEYWORDS:

• FGFR
• inhibitor
• selective
• small molecule
• resistance
• mutation
• fusion
• amplification

Article highlights

• FGFR/FGF is a recurrently altered pathway in human cancers.

• Erdafitinib and Pemigatinib are FDA-approved selective FGFR inhibitors.

• FGFR-selective inhibitors are approved for the treatment of patients with urothelial carcinoma and cholangiocarcinoma.

• Currently available investigational FGFR/FGF inhibitors include small molecule kinase inhibitors, monoclonal antibodies, recombinant peptides, and antibody drug conjugates.

• Secondary kinase domain mutations or MAP kinase/PIK3CA alterations can drive resistance to FGFR inhibitors.

Declaration of interest

G Curigliano has received honoraria for speaker’s engagement: Roche, Seattle Genetics, Novartis, Lilly, Pfizer, Foundation Medicine, NanoString, Samsung, Celltrion, BMS, MSD; Honoraria for providing consultancy: Roche, Seattle Genetics, NanoString; Honoraria for participating in Advisory Board: Roche, Lilly, Pfizer, Foundation Medicine, Samsung, Celltrion, Mylan; Honoraria for writing engagement: Novartis, BMS; Honoraria for participation in Ellipsis Scientific Affairs Group; Institutional research funding for conducting phase I and II clinical trials: Pfizer, Roche, Novartis, Sanofi, Celgene, Servier, Orion, AstraZeneca, Seattle Genetics, AbbVie, Tesaro, BMS, Merck Serono, Merck Sharp Dome, Janssen-Cilag, Philogen, Bayer, Medivation, Medimmune. The author(s) have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer of this manuscript declares serving on an advisory board for: BMS, Genentech, EMD Serono, Merck, Sanofi, Seattle Genetics/Astellas, Astrazeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Immunomedics/Gilead, Scholar Rock, G1 Therapeutics; receiving research support to institution from: Sanofi, Astrazeneca, Immunomedics/Gilead, QED, Predicine, BMS; serving on a steering committee of studies for: BMS, Bavarian Nordic, Seattle Genetics, QED, G1 Therapeutics (all unpaid), and Astrazeneca, EMD Serono, Debiopharm (paid); serving on a data safety monitoring committee for Mereo; receiving travel costs from: BMS (2019), Astrazeneca (2018); receiving writing/editor fees from: Uptodate, Editor of Elsevier Practice Update Bladder Cancer Center of Excellence; receiving speaking fees from: Physicians Education Resource (PER), Onclive, Research to Practice, Medscape (all educational). Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.