Past, present, and future of FGFR inhibitors in cholangiocarcinoma: from biological mechanisms to clinical applications

Introduction: Biliary tract carcinoma (BTC) is a heterogenous group of aggressive hepatic malignancies, second to hepatocellular carcinoma per prevalence. Despite clinical research advancement, the overall 5-year survival rate is just above 2%. With the identification of somatic core mutations in half of cholangiocarcinomas. In the intrahepatic subtype (iCCA), it is possible to target mutational pathways of pharmacological interest. Areas covered: Major attention has been drawn to fibroblast growth factor receptor (FGFR), especially the type 2 (FGFR2), found mutated in 10–15% of iCCAs. FGFR2 fusions became the target of novel tyrosine-kinase inhibitors investigated in clinical studies, showing promising results so as to gain regulatory approval by American and European committees in recent years. Such drugs demonstrated a better impact on the quality of life compared to standard chemotherapy; however, side effects including hyperphosphatemia, gastrointestinal, eye, and nail disorders are common although mostly manageable. Expert opinion: As FGFR inhibitors may soon become the new alternative to standard chemotherapy in FGFR-mutated cholangiocarcinoma, accurate molecular testing and monitoring of acquired resistance mechanisms will be essential. The possible application of FGFR inhibitors in first-line treatment, as well as in combination with current standard treatments, remains the next step to be taken.