New Era of Immune-Based Therapy in Intrahepatic Cholangiocarcinoma

SIMPLE SUMMARY: Intrahepatic cholangiocarcinoma is the second most common primary liver malignancy after hepatocellular carcinoma and accounts for 20% of biliary tract cancers. The incidence of biliary tract cancer has been increasing in recent years, and many patients with biliary tract cancer are diagnosed as unresectable, and, even if resectable, the survival rate is very low. From 2010 to 2021, systemic combination therapy with gemcitabine and cisplatin was the standard therapy for biliary tract cancer. In 2022, the first immunotherapy durvalumab was approved to be added to this combination. As with other solid tumors, immune-based therapies for patients with advanced biliary tract cancer have been shown to have promising outcomes. We discuss the efficacy and safety of these therapies and consider new standards of care. ABSTRACT: Intrahepatic cholangiocarcinoma (CC) accounts for approximately 20% of all biliary tract cancer (BTC) cases and 10–15% of all primary liver cancer cases. Many patients are diagnosed with unresectable BTC, and, even among patients with resectable BTC, the 5-year survival rate is approximately 20%. The BTC incidence rate is high in Southeast and East Asia and has increased worldwide in recent years. Since 2010, cytotoxic chemotherapy, particularly combination gemcitabine + cisplatin (ABC-02 trial), has been the first-line therapy for patients with BTC. In 2022, a multicenter, double-blind, randomized phase 3 trial (TOPAZ-1 trial) examined the addition of programmed death-ligand 1 immunotherapy (durvalumab) to combination gemcitabine + cisplatin for BTC treatment, resulting in significantly improved survival without notable additional toxicity. As a result of this trial, this three-drug combination has become the new standard first-line therapy, leading to notable advances in BTC management for the first time since 2010. The molecular profiling of BTC has continued to drive the development of new targeted therapies for use when first-line therapies fail. Typically, second-line therapy decisions are based on identified genomic alterations in tumor tissue. Mutations in fibroblast growth factor receptor 1/2/3, isocitrate dehydrogenase 1/2, and neurotrophic tyrosine receptor kinase A/B/C are relatively frequent in intrahepatic CC, and precision medicines are available that can target associated pathways. In this review, we suggest strategies for systemic pharmacotherapy with a focus on intrahepatic CC, in addition to presenting the results and safety outcomes of clinical trials evaluating immune checkpoint inhibitor therapies in BTC.