Aimar Giacomo, Paratore Chiara, Zichi Clizia, Marino Donatella, Sperti Elisa, Caglio Andrea, Gamba Teresa, De Vita Francesca, Di Maio Massimo
Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Via Magellano 1, 10128 Turino, Italy.
Explor Target Antitumor Ther. 2021;2(5):448-464. doi: 10.37349/etat.2021.00056. Epub 2021 Oct 31.
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.
不可切除的胆管癌（BTC）患者预后较差，全身化疗后的中位总生存期少于12个月。近年来，通过识别不同的分子改变并采用相应的靶向治疗，正在改变这种治疗策略。本综述的目的是概述BTC的靶向治疗，介绍已发表的可用数据以及正在进行的试验中潜在的未来挑战。2021年7月，从clinicaltrials.gov在线数据库中检索了所有正在进行的BTC（任何阶段）试验，并记录了有关研究设计、疾病特征和治疗类型的数据。在67项试验中研究了致癌驱动疗法（靶向治疗）。根据研究，15项正在进行的试验（22.4%）正在研究BTC中的成纤维细胞生长因子（FGF）受体（FGFR）抑制剂。其中3项（18.7%）是开放标签随机多中心3期试验，8项（50%）是单臂2期试验，4项（25%）是1期研究。12项（17.9%）临床试验涉及异柠檬酸脱氢酶（IDH）1/2靶向治疗，要么与顺铂（Cis）和吉西他滨（Gem）联合作为BTC的一线治疗，要么用于IDH1突变晚期恶性肿瘤患者（包括胆管癌（CCA））的单药治疗。9项（13.4%）临床试验测试了人表皮生长因子受体（HER）2靶向治疗。4项（44.4%）研究是1期试验，2项（22.2%）是1/2期试验，3项（33.3%）是2期试验。BTC中的罕见分子改变，如间变性淋巴瘤激酶（ALK）、c-ros癌基因1受体酪氨酸激酶（ROS1）和v-RAF鼠肉瘤病毒癌基因同源物B1（BRAF），也在少数试验中进行研究。44项临床试验（17.2%）正在研究非致癌驱动的多靶点治疗，如多受体酪氨酸激酶抑制剂和抗血管生成药物。总之，本综述表明，BTC的管理正在经历重大创新，特别是在基于生物标志物的患者选择和新兴治疗方法方面。许多正在进行的试验可能会回答有关分子抑制剂作用的问题，从而为BTC的分子亚类带来新的治疗前沿。
