Clinical complexity of utilizing FGFR inhibitors in cancer therapeutics

ABSTRACT

Introduction

Fibroblast growth factor receptors (FGFR 1–4) are a highly conserved family of receptor tyrosine kinases, involved in several physiological processes. Genetic aberrations of FGFRs and their ligands, fibroblast growth factors (FGFs) are involved in several pathological processes including cancer. The FGF-FGFR axis has emerged as a treatment target in oncology. Because these aberrations drive cancer progression, the development of FGFR targeted therapies have been accelerated.

Areas covered

In this comprehensive review, we evaluate molecular pathology and targeted therapies to FGFRs. We reviewed the evidence for safety and efficacy from preclinical and clinical studies (phase I–III) of FGFR targeted therapies. We also discuss potential challenges in bringing these targeted therapies from bench to bedside and the potential opportunities.

Expert opinion

Despite the challenges of the clinical development of FGFR targeted therapies, two FGFR small-molecule inhibitors, namely Erdafitinib and Pemigatinib, are FDA approved for urothelial cancer and cholangiocarcinoma, respectively. Understanding and detection of FGFR genomic aberrations, protein overexpression and the development of isoform-specific inhibitors are factors in the clinical success of these therapies. An enhanced understanding of patient selection based on a gene signatures or biomarkers is key to success of FGFR targeted therapies.

KEYWORDS:

• Cancer
• fibroblast growth factor receptors
• fibroblast growth factor receptor inhibitors
• fgfr inhibitors
• genetic aberrations
• monoclonal antibodies
• aptamers
• clinical trials
• drug resistance

Article highlights

• FGFR genomic aberrations are relatively rare, but actionable. They are shown to be involved in promoting tumor cell proliferation, survival, drug resistance, angiogenesis and immune evasion.

• Based on current preclinical and clinical data, FGFR gene fusions and mutations are more relevant than amplifications.

• Clinically FGFR fusions and mutations are relatively common and therapeutic targets in solid tumors such as urothelial carcinoma, intrahepatic cholangiocarcinoma, lung cancer, hepatocellular carcinoma, breast cancer and gynecological cancers.

• Several FGFR (1-4) inhibitors (-pan or specific) are in various stages of preclinical and clinical development. Erdafitinib is approved in the treatment of bladder cancer and Pemigatinib is approved for the treatment of cholangiocarcinoma.

• Along with development of FGFR inhibitors, resistance mechanisms and biomarkers and combination with chemotherapy and immunotherapy are being developed

• Development of point of care NGS testing and development of next-generation FGFR inhibitors with less off-target activities, thereby less side effects will be the future in this area targeted therapies.

This box summarizes key points contained in the article.

Acknowledgments

We wish to thank funding from the National Cancer Institute (P30CA023074) grant awarded to the University of Arizona and Mays Cancer Center, University of Texas Health San Antonio (CA054174).

Declaration of interest

SR Chandana received study-related expenses to support to his institution from QED therapeutics. The authors 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

One reviewer receives research funding from AstraZeneca, Tesaro and Merck and has been a consultant to BMS. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.