Broadening the therapeutic horizon of advanced biliary tract cancer through molecular characterisation

Abstract

Biliary tract cancers (BTC) comprise a group of rare and heterogeneous poor-prognosis tumours with the incidence of intrahepatic cholangiocarcinoma increasing over recent years. Combination chemotherapy with gemcitabine and cisplatin is the established first-line treatment for advanced BTC with a significant but modest survival advantage over monotherapy. There remains no accepted standard treatment in the second-line setting, although recent results from a randomised study have shown a survival benefit with 5-fluorouracil and oxaliplatin chemotherapy. Historically, clinical trials investigating targeted therapies in unselected BTC have failed to demonstrate significant clinical benefit. More recently, advancement in molecular exploration of BTC has shed light on the complex biological heterogeneity within these tumours and has also identified actionable genomic aberrations, such as fibroblast growth factor receptor 2 (FGFR2) gene fusions, isocitrate dehydrogenase (IDH) and BRAF mutations, which offer promise with the anticipation of increased responses and durable clinical benefit in selected patients. Several targeted drugs have now entered clinical development with some encouraging results being seen. Here we review the current and rapidly evolving therapeutic landscape of advanced BTC, including targeted therapies and immunotherapy. We also discuss how recent efforts and successes in BTC are overcoming the obstacles typically associated with precision medicine in rare cancers. Ultimately, the management of advanced BTC is likely to become molecularly selected in the near future with the hope of finally improving the bleak prognosis of patients with this disease.

The Efficacy and Safety of Apatinib Plus Camrelizumab in Patients With Previously Treated Advanced Biliary Tract Cancer: A Prospective Clinical Study

“…Camrelizumab (SHR-1210), a PD-1 inhibitor, has been shown to block the binding of PD-1 to PD-L1 and consequently inhibit the immune escape of tumour cells. Therefore, considering the potential synergistic efficacy of targeted therapy combined with immune checkpoint inhibitor, apatinib plus camrelizumab might be a potentially effective combination for various tumors (15). For patients with advanced HCC, apatinib combined with camrelizumab achieved a 34.3% objective response as the first-line and 22.5% as the secondline therapy (16).…”

Bevacizumab based chemotherapy is a promising option in metastatic gallbladder adenocarcinoma

“…Most GBCs do not respond well to chemotherapy with a single agent (13). For locally advanced or metastatic unresectable GBC, gemcitabine and cisplatin based chemotherapy is the recommended treatment option (3,14). Furthermore, chemotherapy in combination with bevacizumab has shown promising results in the treatment of BTCs (15).…”

Futibatinib, an investigational agent for the treatment of intrahepatic cholangiocarcinoma: evidence to date and future perspectives

“…FGFR2 fusion represents the most frequently observed FGFR aberration in iCCA -assessed by FISH or NGS -with a prevalence ranging from 6% to 25% and a mutual exclusivity with KRAS/BRAF mutations [20][21][22][23][24][25][26][27]. Interestingly, FGFR2 fusion-positive iCCA constitutes a distinct molecular subtype of BTC from an immunohistochemical, pathological, and clinical point of view since several reports suggested an association with female predilection, younger age at onset and a more favorable prognosis compared to wild-type patients [21,22]. In the last few years, several trials have evaluated the role of FGFR inhibitors (e.g.…”