Pemigatinib in cholangiocarcinoma with a FGFR2 rearrangement or fusion

ABSTRACT

Introduction

Cholangiocarcinoma (CCA) accounts for approximately 3% of gastrointestinal malignancies and is associated with a high mortality rate. Recent progress in the understanding of cholangiocarcinoma tumorigenesis and molecular markers has led to the development of several targeted therapies applicable to this disease. Fibroblast growth factor receptor 2 (FGFR2) gene fusion or translocation, resulting in constitutive activation of the FGFR tyrosine kinase, has been identified as a driver of oncogenesis in 10–15% of intrahepatic CCA. Pemigatinib is an FGFR inhibitor that has demonstrated survival benefit in the second line setting for treatment of CCA with FGFR2 fusion or rearrangement refractory to chemotherapy. Pemigatinib was the first targeted therapy to be approved by the FDA for treatment of cholangiocarcinoma.

Areas covered

This article reviews FGFR and its dysregulation in oncogenesis, FGFR inhibitors, especially pemigatinib, utilized in treatment of CCA, common adverse events associated with FGFR inhibitors, and future directions in the field of targeted drug development for CCA.

Expert opinion

FGFR inhibitors, including pemigatinib, have shown promise in the management of CCA with FGFR2 fusion or rearrangement; however, acquired resistance remains a major barrier in the field of FGFR inhibitors and requires further study.

KEYWORDS:

• Pemigatinib
• fibroblast growth factor receptor
• FGFR2 fusion
• cholangiocarcinoma

Article highlights

• Fibroblast growth factor receptors (FGFR) are a family of four receptor tyrosine kinases, which play a role in embryonic development, and dysregulation has been implicated in oncogenesis.

• Fibroblast growth factor receptor 2 (FGFR2) fusion or translocation results in constitutive activation of the FGFR tyrosine kinase and has been shown to play a role in oncogenesis of cholangiocarcinoma (CCA).

• Pemigatinib is an FGFR1-3 inhibitor which has shown high response rates in the second line and later setting for the treatment of cholangiocarcinoma with FGFR2 fusion or rearrangement, and a phase 3 trial is currently evaluating its use in the first line setting.

• FGFR inhibitors have a unique set of adverse effects including hyperphosphatemia, ocular toxicity, and nail toxicity, requiring close monitoring and management.

• While FGFR inhibitors have shown promise in treatment of CCA, acquired resistance remains a problem requiring further investigation.

Declaration of interest

The authors have no 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 on this paper has received honoraria from Incyte, Taiho, Servier, AstraZeneca. The remaining reviewers have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

The authors have no funding to report.