Biliary tract carcinomas represent a heterogeneous group of tumours, both at an anatomical and molecular level. 1 Wardell CP Fujita M Yamada T et al. Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations. J Hepatol. 2018; 68: 959-969 Summary Full Text Full Text PDF PubMed Scopus (188) Google Scholar For metastatic biliary tract carcinomas, treatment mainly relies on chemotherapy, which has shown modest but significant results in terms of overall survival. 2 Valle J Wasan H Palmer DH et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010; 362: 1273-1281 Crossref PubMed Scopus (2694) Google Scholar , 3 Lamarca A Palmer DH Wasan HS et al. ABC-06: A randomised phase III, multi-centre, open-label study of active symptom control (ASC) alone or ASC with oxaliplatin / 5-FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally advanced / metastatic biliary tract cancers (ABC) previously-treated with cisplatin/gemcitabine (CisGem) chemotherapy. J Clin Oncol. 2019; 374003 Google Scholar However, although EGFR inhibitors and antiangiogenics failed to show any benefit in addition to chemotherapy (versus chemotherapy alone) in advanced biliary tract carcinomas, 4 Malka D Cervera P Foulon S et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. Lancet Oncol. 2014; 15: 819-828 Summary Full Text Full Text PDF PubMed Scopus (286) Google Scholar , 5 Valle JW Wasan H Lopes A et al. Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial. Lancet Oncol. 2015; 16: 967-978 Summary Full Text Full Text PDF PubMed Scopus (182) Google Scholar genome-wide analyses identified several actionable alterations (eg, IDH1/2, FGFR2, BRAF, HER2, MSI, NTRK) providing novel targets for drug therapies. 6 Farshidfar F Zheng S Gingras M-C et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep. 2017; 18: 2780-2794 Summary Full Text Full Text PDF PubMed Scopus (289) Google Scholar , 7 Javle M Bekaii-Saab T Jain A et al. Biliary cancer: utility of next-generation sequencing for clinical management. Cancer. 2016; 122: 3838-3847 Crossref PubMed Scopus (223) Google Scholar Among them, the genes isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) produce key metabolic enzymes that prevent cell oxidative damage by catalysing the conversion of isocitrate to α-ketoglutarate. Gain-of-function IDH1/2 mutations result in a neomorphic ability to produce the oncometabolite 2-hydroxyglutarate from α-ketoglutarate. 8 Borger DR Tanabe KK Fan KC et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist. 2012; 17: 72-79 Crossref PubMed Scopus (555) Google Scholar The rate of IDH mutations in biliary tract carcinomas ranges from 10 to 20%, the most common mutation in IDH1 occurring mostly in intrahepatic cholangiocarcinomas. 8 Borger DR Tanabe KK Fan KC et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist. 2012; 17: 72-79 Crossref PubMed Scopus (555) Google Scholar Several IDH inhibitors are under investigation in solid tumours, such as the IDH1 inhibitor ivosidenib and the IDH2 inhibitor enasidenib, which have been approved by the US Food and Drug Administration for patients with IDH-mutant relapsed or refractory acute myeloid leukaemia. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 studyProgression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma. Full-Text PDF