Targeting the Fibroblast Growth Factor Receptor (FGFR) in Advanced Cholangiocarcinoma: Clinical Trial Progress and Future Considerations.

Patrick C. Lee,May Cho,Andrew Hendifar,Daneng Li,Jun Gong,Arsen Osipov

doi:10.3390/cancers13071706

Abstract

Simple SummaryCholangiocarcinoma (CCA) is a cancer arising from the bile ducts. Chemotherapy has long been the standard of care for metastatic CCA, but recent clinical trials have shown that fibroblast growth factor receptor (FGFR) inhibitors are a promising new treatment in advanced CCA with documented genetic alterations in FGFR genes. This review provides an overview of the genetic features of CCA, the biology of the FGFR pathway, important FGFR inhibitor clinical trials in CCA, and future opportunities and challenges in the development of FGFR inhibitors for effective clinical use in patients with CCA.Landmark molecular profiling efforts have identified multiple targetable alterations in cholangiocarcinoma. Among the molecular-driven subsets of cholangiocarcinoma, targeting the fibroblast growth factor receptor (FGFR) has shown promise and represents the first targeted therapy to be approved in treatment-refractory, advanced cholangiocarcinoma. In this review, we provide an up-to-date overview of the clinical development of FGFR inhibitors in advanced cholangiocarcinoma. We review the FGFR pathway and discuss emerging issues including resistance to FGFR inhibitors. We end with a discussion on future considerations to optimize the potential of this class of therapeutics in advanced cholangiocarcinoma.

Highlights

Cholangiocarcinomas (CCAs) are comprised of a heterogenous group of cancers that arise from the intra- or extrahepatic bile ducts and constitute the second most common primary liver tumor behind hepatocellular carcinoma [1,2]
NCT02150967 (Phase II), CCA, ≥1 previous n = 83 FGFR2 fusions, ORR 23.1%; include hypophosphatemia, arthralgia, stomatitis, hyponatremia, abdominal pain, and systemic therapy, FGFR2 fusions or rearrange- n = 25 fibroblast growth factor receptor (FGFR) rearrangeORR
FGFR inhibitors represent a therapeutic breakthrough in molecular subsets of advanced CCA in which treatment options are limited, in the second line and higher settings

Summary

Introduction

Cholangiocarcinomas (CCAs) are comprised of a heterogenous group of cancers that arise from the intra- or extrahepatic bile ducts and constitute the second most common primary liver tumor behind hepatocellular carcinoma [1,2]. CCA is classically categorized into intrahepatic (iCCA) and extrahepatic cholangiocarcinoma (eCCA) with separation by the second order bile ducts [1]. Extrahepatic CCA can be further divided into hilar (Klatskin) or perihilar and distal tumors, as separated by the insertion of the cystic duct. The majority of CCAs are hilar (~60%) followed by distal tumors (20–30%) and intrahepatic tumors (5–10%) there has been a progressive global increase in incidence and mortality for iCCA [1,2,4,5]

Results

Discussion

Conclusion