Targeted mutation-based therapy for intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive primary liver cancer with limited treatment options and poor prognosis. Although gemcitabine combined with cisplatin (GEMCIS) or newly GEMCIS plus durvalumab is the first-line systemic therapy for iCCA, several promising treatment targets have been identified in the past decade in both first- and subsequent-line settings, including neurotrophic tropomyosin-receptor tyrosine kinase (NTRK) fusions, RET fusions, high microsatellite instability (MSI-H), high tumor mutation burden (TMB-H), as well as fibroblast growth factor receptor 2 (FGFR2) fusions, BRAF V600E mutation, isocitrate dehydrogenase (IDH)-1 and IDH-2 mutations, and human epidermal growth factor receptor 2 [HER2 (ERBB2)] amplifications. Corresponding small molecule inhibitors and monoclonal antibodies have demonstrated improved efficacy and survival benefits in phase 2 or phase 3 studies, gained regulatory approvals or recommendations in guidelines, and reshaped the therapeutic management for advanced cholangiocarcinoma. Numerous novel targeted drugs and combination therapies have been developed and are under evaluation. Despite the progress made in targeted therapy, it still faces challenges such as acquired drug resistance, precise patient selection, and serious adverse events. Therefore, large-scale randomized phase 3 trials of novel targeted agents and innovative regimens are warranted to benefit this population. Herein, we present a comprehensive review of the literature of clinical significance on targeted therapy for iCCA in recent years, focusing on the advances in mutation-based targeted therapy.