Integrating cytotoxic, targeted and immune therapies for cholangiocarcinoma

Management of biliary tract cancers (BTCs) is rapidly evolving. The majority of patients are diagnosed with advanced disease. In this setting, chemotherapy with cisplatin and gemcitabine (with durvalumab) followed by second-line FOLFOX is the cornerstone of treatment. Targeted therapies for tumours harbouring FGFR2 fusions, IDH1 mutations, BRAF V600E mutations, NTRK fusions and/or HER2 (ERBB2) amplifications, among others, have brought precision medicine to the forefront of management of advanced BTC. This holds especially true for patients with intrahepatic cholangiocarcinoma. Recently, immunotherapy, especially combined with chemoterapy, has also shown promising activity. The field is now moving forward – management is no longer limited to chemotherapy or targeted therapies alone, with increasing research focused on how combination strategies could enhance therapeutic responses. We are therefore facing a change of paradigm, where immunotherapy, cytotoxic chemotherapy and targeted therapies will be administered concomitantly with the aim of harnessing potential synergies. This review will focus on the rationale behind these combinations and summarise current clinical trial data.