The future of fibroblast growth factor receptor inhibitors and mechanisms of resistance for cholangiocarcinoma

ABSTRACT

Introduction

Cholangiocarcinoma (CCA) is a rare cancer that arises from the biliary tract. Despite advances in multimodal treatment, patients with CCA have a poor prognosis. Molecular profiling of CCA has identified unique genetic aberrations (GA) that may serve as therapeutic targets. A common GA in CCA is in the fibroblast growth factor receptors (FGFR). FGFRs are a group of transmembrane receptors that stimulate downstream pathways for cell proliferation and survival.

Areas covered

We herein review recent clinical trial data related to different FGFR inhibitors and the challenges within the field. An extensive literature search was performed to identify preclinical studies, clinical research, and clinical trials that evaluated the effectiveness of FGFR inhibitor therapy in patients with CCA.

Expert opinion

FGFR inhibitors have demonstrated effectiveness in pre-clinical studies and some clinical trials. Infigratinib, futibatinib, and pemigatinib are being evaluated in an open phase III trial versus gemcitabine/cisplatin as first-line treatment for locally advanced or metastatic CCA with FGFR GA (PROOF-301 NCT03773302, FOENIX-CCA3 NCT04093362, FIGHT-302 NCT03656536). Unfortunately, the effectiveness of FGFR therapy is often limited by acquired resistance mechanisms, and continued work is needed to understand and overcome these mechanisms of resistance.

KEYWORDS:

• Cholangiocarcinoma
• fibroblast growth factor receptor
• FGFR
• targeted therapy
• biliary tract cancer

Article highlights

• Cholangiocarcinoma is a rare cancer that arises from the biliary tract and is anatomically defined as intrahepatic or extrahepatic.

• For patients with resectable disease, upfront surgery and adjuvant capecitabine is the standard of care. If patients present with advanced or metastatic disease, first-line therapy is generally gemcitabine/cisplatin. Unfortunately, treatment with traditional systemic chemotherapy is often not effective.

• Genomic profiling of cholangiocarcinomas has identified unique genetic aberrations that may be promising therapeutic targets.

• Fibroblast growth factor receptors (FGFRs) are a group of transmembrane receptors with an intracellular tyrosine kinase. Downstream pathways induce cell proliferation and survival.

• Approximately 10–15% of patients with cholangiocarcinoma contain genetic aberrations in FGFR, primarily in intrahepatic cholangiocarcinomas.

• FGFR inhibitors have had limited success in phase II clinical trials as second-line therapy in treating patients with advanced or metastatic intrahepatic cholangiocarcinoma, primarily in patients with FGFR2 genetic aberrations. The effectiveness of therapy is often limited, however, by acquired resistance mechanisms.

• Several current trials are evaluating the use of FGFR inhibitors versus gemcitabine/cisplatin as upfront therapy for advanced or metastatic cholangiocarcinoma. Pre-clinical and clinical investigations seek to understand the mechanisms of FGFR resistance.

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

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.