Abstract
Biliary tract cancer (BTC) compromises a heterogenous group of tumors with poor prognoses. Curative surgery remains the first choice for localized disease; however, most BTC patients have had unresectable or metastatic disease. The gold standard therapy for these patients is chemotherapy with gemcitabine and cisplatin. There are no consensus guidelines for standard treatment in a second-line setting, although the data of the ABC-06 trial showed a slight survival benefit from oxaliplatin and 5-fluorouracil combination chemotherapy. Recent progress in comprehensive genomic profiling for advanced BTC (ABTC) has helped to clarify tumorigenesis and facilitate the coming era of precision medicine. Generally, targeted agents fail to show significant clinical benefits in unselected populations. Only fibroblast growth factor receptor 2 (FGFR2) fusion and isocitrate dehydrogenase (IDH)- and BRAF mutation-enriched populations have survival benefits from the corresponding inhibitors. Several interesting targeted agents for monotherapies or combination therapies with other compounds are currently ongoing or recruiting. Here, we review the published data from clinical trials of second-line therapies after the failure of gemcitabine-based chemotherapy in ABTC. The results were stratified by different genetic alternations, as well as by chemotherapy, targeted therapy and immunotherapy.
Highlights
These studies have identified new, recurrent driver genetic alternations in cholangiocarcinoma, such as fibroblast growth factor receptor 2 (FGFR2) fusion and IDH1 mutations that are potentially actionable with available pan-FGFR inhibitors and IDH1 inhibitors [16,17,18]
This study shows the clinical benefit of ivosidenib in advanced, IDH1-mutant cholangiocarcinoma
The results indicated that D + T have promising efficacy in patients with advanced BTC (ABTC), as well as favorable safety profile [89]
Summary
A randomized phase III JCOG 1113 study showed the noninferiority of gemcitabine and S-1 (GS) to GC with a numerical median OS (15.1 months vs 13.4 months), which met pre-planned statistical design [10] Based on these results, GS can be considered an alternative regimen for ABTC patients who would not be tolerant to vigorous hydration or cisplatin-related toxicities. The recent whole-exome and targeted sequencing of BTC confirmed the frequent mutations in well-known genes including TP53, KRAS and IDH1/2 and revealed mutations in novel chromatin remodelling-associated genes, such as BAP1, ARID1A and PBRM1 [15] These studies have identified new, recurrent driver genetic alternations in cholangiocarcinoma, such as FGFR2 fusion and IDH1 mutations that are potentially actionable with available pan-FGFR inhibitors and IDH1 inhibitors [16,17,18].
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