Biliary tract cancers (BTCs), comprising intrahepatic, perihilar, and distal
cholangiocarcinoma as well as gallbladder
adenocarcinoma, continue to be challenging to manage. Conventional
chemotherapy regimens for advanced disease are limited in both options and benefits, and more effective perioperative regimens are also needed. Over the last decade,
immunotherapy has had a profound impact on the management of many solid
tumor types, particularly in using
immune checkpoint inhibition to enable a
tumor-directed T cell response.
Immunotherapy administered on its own has had limited utility in BTCs, in part due to a hostile immune microenvironment and the relative infrequency of
biomarker-based
tumor-agnostic indications for
immunotherapy. However,
immunotherapy in conjunction with
chemotherapy, molecularly targeted
therapies, and/or anti-angiogenic
therapies has gained
traction, supported by evidence that these agents can impart favorable immunomodulatory effects on the tumor microenvironment. The TOPAZ-1 trial led to the first BTC-specific
immunotherapy approval, establishing the combination of
durvalumab with
gemcitabine and
cisplatin as the preferred first-line treatment for advanced or metastatic disease. Recently, the KEYNOTE-966 trial showed positive results for the combination of
pembrolizumab with
gemcitabine and
cisplatin in the same setting, adding further evidence for the addition of
immune checkpoint inhibition to the standard
chemotherapy backbone. Meanwhile, advances in the molecular profiling of BTCs has contributed to the recent proliferation of molecularly targeted
therapeutics for the subset of BTCs harboring alterations in IDH1, FGFR2, MAP
kinase signaling, HER2, and beyond, and there has been great interest in investigating combinations of these agents with
immunotherapy. Emerging
immunotherapy strategies beyond
immune checkpoint inhibition are also being studied in BTCs, and these include immunostimulatory receptor agonists, Wnt signaling modulators, adoptive
cell therapy, and
cancer vaccines. A large number of trials are underway to explore promising new combinations and immune-targeted strategies, offering opportunities to expand the role of
immunotherapy in BTC management in the near future.