Rational development of combination therapies for biliary tract cancers

Biliary tract cancers are an uncommon set of gastrointestinal malignancies that are associated with high morbidity and mortality rates. 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 and combination treatments are now applied as both standard-of-care and investigational therapies. In the first-line setting, the immune-based chemotherapy combination of durvalumab plus gemcitabine and cisplatin has recently been shown to improve survival compared to chemotherapy alone. In the second-line, precision medicine can be employed in those with select genetic alterations in IDH1/2 (isocitrate dehydrogenase 1/2), FGFR2 (fibroblast growth factor receptor 2), KRAS, BRAF, ERBB2, NTRK (neurotrophic receptor tyrosine kinase), ROS, RET, and/or deficiencies in mismatch repair enzymes. In those patients without targetable genetic alterations, fluoropyridine doublets lead to modest improvements in outcomes. Next-generation sequencing is critical for direct patient care and to help elucidate genomic mechanisms of resistance in a research context. Currently, multiple clinical trials are ongoing - hence, 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.