Targeting FGFR in intrahepatic cholangiocarcinoma [iCCA]: leading the way for precision medicine in biliary tract cancer [BTC]?

ABSTRACT

Introduction: The increasing availability of next-generation DNA sequencing (NGS) opens the opportunity to tailor therapies to potential targets. Intrahepatic cholangiocarcinoma (iCCA) has the most actionable genomic targets of the hepatobiliary malignancies, including mutations in Isocitrate Dehydrogenase (IDH) and Fibroblast Growth Factor Receptor (FGFR), particularly FGFR2. With the recent accelerated approval of pemigatinib and several trials currently underway, FGFR2 inhibition will set the mold for tailored therapies in hepatobiliary cancer.

Areas covered: We review the current standard of therapy for iCCA, the genomic targets, and the role of FGFR inhibitors in developing the treatment landscape. The FGFR mechanism of actionand use of IDH1/2 inhibition and immunotherapy in iCCA are also discussed. We queried the PubMed and ClinicalTrials.gov databases, along with conference proceedings for relevant data.

Expert opinion: While more mature data are needed from the trials in progress, currently published analyses show survival benefit with FGFR2 inhibitors in patients positive for FGFR2 fusion who have failed the standard of care. Infigratinib, futibatinib, pemigatinib and derazantinib have all demonstrated promising activity iCCA patients harboring FGFR2 fusion. Eventually, head-to-head trials will be needed to fully understand the benefits of each agent and the role of reversible versus irreversible FGFR2 inhibitors.

KEYWORDS:

• Targeted therapy
• genomic sequencing
• pemigatinib
• next-generation sequencing
• liver cancer
• cholangiocarcinoma
• intrahepatic cholangiocarcinoma
• FGFR

Article highlights

• Intrahepatic cholangiocarcinoma (iCCA) has the most potential actionable genomic targets of the hepatobiliary malignancies with mutations in isocitrate dehydrogenase 1 (IDH1) and fibroblast growth factor receptor 2 (FGFR2) appearing to be some of the most unique to the disease.

• Data from the phase II trials for infigratinib, pemigatinib, futibatinib, and derazantinib have proved to be promising options in patients with advanced disease who failed first-line therapy, particularly in those with FGFR2 fusion mutations.

• The recent accelerated FDA approval of pemigatinib with anticipated approvals of futibatinib and infigratinib will vastly expand options for this subset of patients.

• Further exploration is warranted into the role of resistance in the efficacy of reversible (infigratinib, pemigatinib, and derazantinib) and irreversible (futibatinib) FGFR2 inhibitors as well as head-to-head studies of drug efficacy against the standard of care.

• Given the more widespread use of next-generation DNA sequencing (NGS) in the clinic setting, the opportunity to apply the process of identifying of FGFR2 mutations and subsequently utilizing FGFR2 inhibitors will provide the model for greater implementation in the treatment of hepatobiliary malignancies.

This box summarizes key points contained in the article.

Abbreviations

AASLD: American Association for the Study of Liver Diseases; ap-CAFs: antigen-presenting CAFs; ARAF: Serine/threonine-protein kinase A-Raf; ARID1A: AT-rich interactive domain 1A; ASCO: American Society of Clinical Oncology; AVC: ampulla of Vater cancer; BAP1: BRCA1-associated Protein-1; BRCA1: breast cancer 1; BTC: biliary tract cancer; CCA: cholangiocarcinoma; CDK6: cyclin-dependent kinase; CDKN2A: CDK inhibitor 2A; DCR: disease control rate; DOR: duration of response; EASL: European Association for the Study of the Liver; eCCA: extrahepatic cholangiocarcinoma; ECM: extracellular matrix; ECOG: Eastern Cooperative Oncology Group; ELF3: E74-like ETS transcription factor 3; EMT: Epithelial-mesenchymal transition; EPHA2: Ephrin type-A receptor 2; ERBB3: epidermal growth factor receptor 3; ESMO: European Society for Medical Oncology; EZH2: enhancer of zeste homolog 2; FGFR: Fibroblast Growth Factor Receptor; FOLFOX: folinic acid, 5-fluorouracil, and oxaliplatin; GBC: gallbladder cancer; gem-cis: gemcitabine-cisplatin; HCC: hepatocellular carcinoma; HR: hazard ratio; iCAF: inflammatory CAFs; ICCA: Intrahepatic cholangiocarcinoma; IDH: Isocitrate Dehydrogenase; KRAS: Kristen ras sarcoma viral oncogene homolog; mCAF: matrix CAFs; mOS: Median overall survival; NF1: Neurofibromin 1; NGS: next-generation DNA sequencing; NRAS: neuroblastoma RAS viral oncogene homolog; ORR: objective response rate; PBRM1: Polybromo 1; PD-1: programmed cell death protein 1; PFS: progression-free survival; PI3K-AKT-mTOR: phosphoinositide 3-kinase/protein kinase B/mammalian target of; rapamycin PI3KCA: phosphoinositide-3-kinase, catalytic, alpha polypeptide; PRKAC: protein kinase A CAMP-activated catalytic subunit; PRKACA: protein kinase A CAMP-activated catalytic alpha subunit; PRKACB: protein kinase A CAMP-activated catalytic beta; PTCH1: patched homolog 1; PTEN: phosphatase and tensin homolog; RAS-MAPK: RAS/mitogen-activated protein kinase; RECIST v1.1: Response Evaluation Criteria in Solid Tumors version 1.1; SEER: Surveillance, Epidemiology, and End Results; TCGA: US National Cancer Institute’s Cancer Genome Atlas; TP53: Tumor protein p53; TSC1: Tuberous sclerosis 1; vCAF: vascular cancer-associated fibroblasts

Disclaimer

The authors prepared this work in their personal capacity. The opinions expressed in this article are the author’s own and do not reflect the view of the Department of Veterans Affairs or the United States government.

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

One referee has received honoraria for consultation with Taiho, Incyte and Basilea.

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

Additional information

Funding

This paper was not funded.