Gupta Amol, Kurzrock Razelle, Adashek Jacob J
Department of Medicine, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, MD 21287, USA.
WIN Consortium, San Diego, CA 92093, USA.
Cancers (Basel). 2023 Mar 3;15(5):1578. doi: 10.3390/cancers15051578.
In the past two decades, molecular targeted therapy has revolutionized the treatment landscape of several malignancies. Lethal malignancies such as non-small cell lung cancer (NSCLC) have become a model for precision-matched immune- and gene-targeted therapies. Multiple small subgroups of NSCLC defined by their genomic aberrations are now recognized; remarkably, taken together, almost 70% of NSCLCs now have a druggable anomaly. Cholangiocarcinoma (CCA) is a rare tumor with a poor prognosis. Novel molecular alterations have been recently identified in patients with CCA, and the potential for targeted therapy is being realized. In 2019, a fibroblast growth factor receptor 2 () inhibitor, pemigatinib, was the first approved targeted therapy for patients with locally advanced or metastatic intrahepatic CCA who had gene fusions or rearrangement. More regulatory approvals for matched targeted therapies as second-line or subsequent treatments in advanced CCA followed, including additional drugs that target gene fusion/rearrangement. Recent tumor-agnostic approvals include (but are not limited to) drugs that target mutations/rearrangements in the following genes and are hence applicable to CCA: isocitrate dehydrogenase 1 (); neurotrophic tropomyosin-receptor kinase (); the V600E mutation of the gene (); and high tumor mutational burden, high microsatellite instability, and gene mismatch repair-deficient (TMB-H/MSI-H/dMMR) tumors. Ongoing trials investigate HER2, , and non- mutations in CCA and improvements in the efficacy and safety of new targeted treatments. This review aims to present the current status of molecularly matched targeted therapy for advanced CCA.
在过去二十年中，分子靶向治疗彻底改变了多种恶性肿瘤的治疗格局。非小细胞肺癌（NSCLC）等致命性恶性肿瘤已成为精准匹配免疫治疗和基因靶向治疗的典范。现在已识别出多个由基因组畸变定义的非小细胞肺癌小亚组；值得注意的是，总体而言，近70%的非小细胞肺癌现在存在可靶向治疗的异常情况。胆管癌（CCA）是一种预后较差的罕见肿瘤。最近在胆管癌患者中发现了新的分子改变，靶向治疗的潜力正在得到实现。2019年，成纤维细胞生长因子受体2（FGFR2）抑制剂培米替尼成为首个被批准用于治疗具有FGFR2基因融合或重排的局部晚期或转移性肝内胆管癌患者的靶向疗法。随后，更多针对晚期胆管癌二线或后续治疗的匹配靶向疗法获得监管批准，包括其他靶向FGFR2基因融合/重排的药物。最近的肿瘤非特异性批准包括（但不限于）靶向以下基因的突变/重排且因此适用于胆管癌的药物：异柠檬酸脱氢酶1（IDH1）；神经营养性原肌球蛋白受体激酶（NTRK）；BRAF基因的V600E突变（BRAF V600E）；以及高肿瘤突变负荷、高微卫星不稳定性和错配修复缺陷（TMB-H/MSI-H/dMMR）肿瘤。正在进行的试验研究胆管癌中的HER2、NTRK和非BRAF突变，以及新靶向治疗的疗效和安全性的改善。本综述旨在介绍晚期胆管癌分子匹配靶向治疗的现状。
