A review of molecularly targeted therapy in biliary tract carcinoma: what is the next step?

Abstract

Patients with unresectable biliary tract carcinomas (BTCs) have a poor prognosis with a median overall survival of fewer than 12 months following systemic chemotherapy. In recent years, the identification of distinct molecular alterations with corresponding targeted therapies is modifying this therapeutic algorithm. The aim of this review is to present an overview of targeted therapy for BTCs, describing published available data and potential future challenges in ongoing trials. From clinicaltrials.gov online database all ongoing trials for BTCs (any stage) was examinated in July 2021, and data regarding study design, disease characteristics and type of treatments were registered. Oncogenic-driven therapy (targeted therapy) was investigated in 67 trials. According to research, 15 ongoing trials (22.4%) are investigating fibroblast growth factor (FGF) receptor (FGFR)-inhibitors in BTCs. Three (18.7%) are open-label randomized multicenter phase 3 trials, 8 (50%) are single-arm phase two trials, and 4 (25%) are phase one studies. Twelve (17.9%) clinical trials dealt with isocitrate dehydrogenase (IDH) 1/2 targeting therapy either in combination with cisplatin (Cis) and gemcitabine (Gem) as first-line treatment for BTCs or in monotherapy in patients with IDH1 mutant advanced malignancies, including cholangiocarcinoma (CCA). Nine (13.4%) clinical trials tested human epidermal growth factor receptor (HER) 2 targeting therapy. Four (44.4%) studies are phase I trials, two (22.2%) are phase I/II trials, and three (33.3%) phase II trials. Rare molecular alterations in BTCs, such as anaplastic lymphoma kinase (ALK), c-ros oncogene1 receptor tyrosine kinase (ROS1), and v-RAF murine sarcoma viral oncogene homologue B1 (BRAF), are also under investigation in a few trials. Forty-four clinical trials (17.2%) are investigating not oncogenic-driven multitarget therapy like multireceptor tyrosin kinase inhibitors and antiangiogenetic agents. In conclusion, this review shows that BTCs management is experiencing important innovations, especially in biomarker-based patient selection and in the new emerging therapeutic approach. Many ongoing trials could answer questions regarding the role of molecular inhibitors leading to new therapeutic frontiers for molecular subcategories of BTCs.

An unresectable and metastatic intrahepatic cholangiocarcinoma with EML4-ALK rearrangement achieving partial response after first-line treatment with ensartinib: a case report

“…Currently, the clinical evidence of ALK fusion proteins in cancer largely originates from ALK-positive NSCLC, but there are scarce data regarding the incidence and targeted therapy of ALK rearrangements in cholangiocarcinoma. Several studies showed that ALK rearrangements are found in <1% of cholangiocarcinoma patients (9)(10)(11). A retrospective analysis evaluated the predictive significance of ALK, c-ros oncogene1 receptor tyrosine kinase (ROS1), or mesenchymal to epithelial transition (MET) aberrant expression (RAM) in advanced or metastatic biliary tract cancer patients treated with gemcitabine plus oxaliplatin with or without cetuximab, and found that all RAM-high (immunohistochemistry intensity 3+ for any markers) tumors derived from ICC patients, who had shorter OS than RAM-low (immunohistochemistry intensity <3+ for all markers) ICC patients (median OS, 5.7 vs. 11.7 months, P=0.021) (12).…”

Efficacy of dual checkpoint inhibitors in a patient with a mixed hepatocellular cholangiocarcinoma

“…The main treatment options for biliary tract cancers are surgery and systemic therapy, the former being the only potentially curative option 13. Due to the often-advanced stage at the time of disease presentation, only 10%–15% of these tumours are amenable to surgery.…”

“…Due to the often-advanced stage at the time of disease presentation, only 10%–15% of these tumours are amenable to surgery. Even these early-stage tumours have an elevated recurrence rate and a 5-year survival between 8% and 30% 13 14. The ABC-02 trial in 2010 established gemcitabine plus cisplatin as the preferred regimen for unresectable and metastatic disease 15.…”

Immunotherapy for Biliary Tract Cancer in the Era of Precision Medicine: Current Knowledge and Future Perspectives

“…To date, the only potentially curative treatment is represented by radical surgery. Unfortunately, only 10–15% of tumors at diagnosis are amenable to surgical treatments, with a high rate of recurrence and a five-year survival of 8–30% [ 5 , 6 ]. For a long time, cholangiocarcinoma has been considered an orphan disease with very limited therapeutic options.…”