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

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.