Targetable Molecular Alterations in the Treatment of Biliary Tract Cancers: An Overview of the Available Treatments

SIMPLE SUMMARY: Biliary tract cancers (BTCs) are rare tumours associated with poor prognosis. In advanced-stage disease, two treatment lines are approved: gemcitabine-cisplatin in combination with checkpoint inhibitors, and 5-FU-oxaliplatin, with a median overall survival of approximately one year. About 40% of BTC bear a targetable molecular alteration, the most frequent being FGFR2 fusions and IDH1 mutations in about 15% of intrahepatic cholangiocarcinomas. In this review, we will describe the different molecular targetable alterations in BTC (including FGFR2 and NTRK fusions, IDH1 mutation, BRAFV600E mutation, HER2 amplification, BRCA1/2 mutation and KRASG12C mutation), the targeted therapies that these patients can receive and the expected benefit. ABSTRACT: Biliary tract cancers (BTCs) are rare tumours, most often diagnosed at an unresectable stage, associated with poor prognosis, with a 5-year survival rate not exceeding 10%. Only first- and second-line treatments are well codified with the combination of cisplatin-gemcitabine chemotherapy and immunotherapy followed by 5-FU and oxaliplatin chemotherapy, respectively. Many studies have shown that BTC, and more particularly intrahepatic cholangiocarcinoma (iCCA), have a high rate of targetable somatic alteration. To date, the FDA has approved several drugs. Ivosidenib targeting IDH1 mutations, as well as futibatinib and pemigatinib targeting FGFR2 fusions, are approved for pre-treated advanced CCA. The combination of dabrafenib and trametinib are approved for BRAFV600E mutated advanced tumours, NTRK inhibitors entrectinib and larotrectinib for tumours bearing NTRK fusion and prembrolizumab for MSI-H advanced tumours, involving a small percentage of BTC in these three settings. Several other potentially targetable alterations are found in BTC, such as HER2 mutations or amplifications or KRASG12C mutations and mutations in genes involved in DNA repair mechanisms. This review aims to clarify the specific diagnostic modalities for gene alterations and to summarize the results of the main trials and developments underway for the management of advanced BTC with targetable alterations.