Rational Development of Combination Therapies in Biliary Tract Cancers

Biliary tract cancers are an uncommon set of gastrointestinal malignancies with a high morbidity and mortality. Most patients present with incurable locally advanced or metastatic disease. The pathophysiology of biliary tract cancer can be exploited for direct therapeutic benefit, and indeed, chemotherapy, precision medicine, immunotherapy as well as combination treatments are now applied as both standard-of-care and investigational therapy. In the first-line setting, the immune-based chemotherapy combination of durvalumab plus gemcitabine and cisplatin has recently shown to offer superior survival to chemotherapy alone. In the second-line, precision medicine can be employed in those patients with select genetic alterations in IDH1, FGFR2, KRAS, BRAF, ERBB2, NTRK, ROS, RET, and in mismatch repair deficiency or microsatellite instability. In those patients without gene alterations, fluoropyridine doublets have shown only modest improvements in outcomes. Next generation sequencing is critical for direct patient care, as well in a research context to help clarify genomic mechanisms of resistance. Currently, multiple clinical trials at various stages are ongoing and this review seeks to provide an update on evolving standards of care and ongoing investigational agents, limitations to current treatments, and a framework for effective combination drug development for the future.