Changing Landscape of Systemic Therapy in Biliary Tract Cancer

SIMPLE SUMMARY: Cancers from the bile ducts and gall bladder are lethal. Cure by surgery is not possible in most of these tumors as they are often identified in later stages. Unlike other cancers, they have few chemotherapy treatment options. Multiple clinical trials in the past decade failed and could not replace the combination of two drugs, gemcitabine and cisplatin, as the preferred drug in new cases. Patients who fail to respond to this combination do not have reliable treatment options. The success of therapy directed at a specific genetic change (mutation) and activating the patient’s immune system (alone or in combination with chemotherapy) are encouraging. If we follow the current trials, the focus is on these newer treatments, with there being a high chance they may replace traditional chemotherapy in the future. ABSTRACT: Biliary tract cancers (BTC) are often diagnosed at advanced stages and have a grave outcome due to limited systemic options. Gemcitabine and cisplatin combination (GC) has been the first-line standard for more than a decade. Second-line chemotherapy (CT) options are limited. Targeted therapy or TT (fibroblast growth factor 2 inhibitors or FGFR2, isocitrate dehydrogenase 1 or IDH-1, and neurotrophic tyrosine receptor kinase or NTRK gene fusions inhibitors) have had reasonable success, but <5% of total BTC patients are eligible for them. The use of immune checkpoint inhibitors (ICI) such as pembrolizumab is restricted to microsatellite instability high (MSI-H) patients in the first line. The success of the TOPAZ-1 trial (GC plus durvalumab) is promising, with numerous trials underway that might soon bring targeted therapy (pemigatinib and infrigatinib) and ICI combinations (with CT or TT in microsatellite stable cancers) in the first line. Newer targets and newer agents for established targets are being investigated, and this may change the BTC management landscape in the coming years from traditional CT to individualized therapy (TT) or ICI-centered combinations. The latter group may occupy major space in BTC management due to the paucity of targetable mutations and a greater toxicity profile.