LAUSR

Cholangiocarcinoma (CCA), the most common biliary tract malignancy, represents a heterogeneous group of epithelial cancers arising from varying locations within the biliary tree. The anatomical subtypes of CCA are intrahepatic CCA (iCCA), which arises in the liver parenchyma above the second-order bile ducts, perihilar CCA, which arises from the large bile ducts in the hepatic hilum and above the insertion of the cystic duct, and distal CCA, which arises below the insertion of the cystic duct.(1) The different anatomical subtypes are unified by delayed diagnosis and consequently poor outcomes as potentially curative surgical options are limited to early-stage disease. The practice standard for patients with advanced/unresectable disease is systemic chemotherapy with gemcitabine and cisplatin, which has limited efficacy (median overall survival, 11.7 months).(1) Currently, there are no approved medical therapies for CCA patients who have progressive disease despite gemcitabine/cisplatin therapy. Moreover, nontargeted therapies have poor efficacy in advanced CCA. The CCA subtypes have divergent biological behaviors with each having a distinct mutational landscape. For instance, fibroblast growth factor receptor (FGFR) the detection of anaplastic lymphoma kinase (ALK) gene fusions in lung cancer has led to accelerated approval of therapies for ALK-positive lung cancer. Hence, discovery of the FGFR2 gene fusions in iCCA has garnered much excitement, and there are several FGFR inhibitors being evaluated in clinical trials of CCA patients with tumors containing FGFR2 gene fusions. These include BGJ398, TAS-120, E7090, and ARQ-087. E7090 is a selective FGFR inhibitor being evaluated in phase I clinical trial in patients with advanced solid tumors (NCT02275910). In a phase 1/2 clinical trial (NCT01752920) of patients with advanced solid tumors, ARQ-087 had encouraging antitumor activity in the subset of patients with iCCA (n = 30), with a partial response in 6 patients (20%) and stable disease in 17 (57%).(4) BGJ398 has been the most extensively studied FGFR inhibitor in human clinical trials. BGJ398 is an orally bioavailable, small-molecule, selective pan-FGFR inhibitor, which has demonstrated antitumor activity in preclinical models of CCA.(1) In a phase 1, dose-escalation, and dose-expansion study, BGJ398 was evaluated in 132 patients with advanced solid organ malignancies containing FGFR genetic