晚期胆道肿瘤药物治疗研究进展

doi:10.3760/cma.j.cn371439-20200304-00104

摘要/Abstract

摘要：

晚期胆道肿瘤患者中位生存期不足1年,化疗仍然是其主要治疗手段。近年来,新型分子靶向疗法和免疫疗法在晚期胆道肿瘤领域得以广泛研究。其中,成纤维细胞生长因子受体抑制剂、抗血管生成药物、c-Met抑制剂等新药治疗晚期胆道肿瘤获得了令人鼓舞的疗效。免疫检查点抑制剂和双功能免疫新药为晚期胆道肿瘤患者的治疗带来了希望。一些在研Ⅲ期临床研究有望改变晚期胆道肿瘤临床治疗现状,为患者带来更多生存获益。

关键词: 胆道肿瘤, 分子靶向治疗, 免疫疗法, 生存

Abstract:

The median overall survival is shorter than 1 year and chemotherapy is still the main treatment for patients with metastatic biliary tract cancer (BTC). Over the recent years, novel molecular targeted therapy and immunotherapy have been extensively tested in this disease. Among them, fibroblast growth factor receptors inhibitors, anti-vasculature therapy and c-Met inhibitors and other new drugs have achieved encouraging curative effect in the treatment of metastatic BTC. Meanwhile, immune checkpoint inhibitors and bifunctional immune agents hold great promise for this type of cancers. Some ongoing phase Ⅲ trials may change the clinical status and improve the outcome for patients with metastatic BTC.

Key words: Biliary tract neoplasms, Molecular targeted therapy, Immunotherapy, Survivorship

刘小军, 李淑萍, 王巍. 晚期胆道肿瘤药物治疗研究进展[J]. 国际肿瘤学杂志, 2020, 47(11): 700-704.

Liu Xiaojun, Li Shuping, Wang Wei. Drug treatment advances towards metastatic biliary tract cancer[J]. Journal of International Oncology, 2020, 47(11): 700-704.

参考文献 35

[1]	雷道雄, 王凤飚, 刘森. 原发性肝内胆管癌的临床病理特征与外科策略[J]. 国际肿瘤学杂志, 2015,42(1):60-63. DOI: 10.3760/cma.j.issn.1673-422X.2015.01.016.
[2]	陈昆仑, 翟文龙. 胆管癌的治疗现状[J]. 中华肝脏外科手术学电子杂志, 2017,6(6):447-449. DOI: 10.3877/cma.j.issn.2095-3232.2017.06.007.
[3]	Ji JH, Kim YS, Park I, et al. Chemotherapy versus best supportive care in advanced biliary tract carcinoma: a multi-institutional propensity score matching analysis[J]. Cancer Res Treat, 2018,50(3):791-800. DOI: 10.4143/crt.2017.044. doi: 10.4143/crt.2017.044 pmid: 28838033
[4]	Lamarca A, Palmer DH, Wasan HS, et al. ABC-06 \| A randomised phase Ⅲ, multi-centre, open-label study of active symptom control (ASC) alone or ASC with oxaliplatin / 5-FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally advanced / metastatic biliary tract cancers (ABC) previously-treated with cisplatin/gemcitabine (CisGem) chemotherapy[J]. J Clin Oncol, 2019,37(15_suppl):4003. DOI: 10.1200/JCO.2019.37.15_suppl.4003.
[5]	宗源, 周军, 沈琳. 晚期胆管癌的药物治疗现状[J]. 中华临床医师杂志(电子版), 2019,13(3):214-220. DOI: 10.3877/cma.j.issn.1674-0785.2019.03.012.
[6]	Deleon TT, Ahn DH, Bogenberger JM, et al. Novel targeted therapy strategies for biliary tract cancers and hepatocellular carcinoma[J]. Future Oncol, 2018,14(6):553-566. DOI: 10.2217/fon-2017-0451. doi: 10.2217/fon-2017-0451 pmid: 29460642
[7]	Silverman IM, Murugesan K, Lihou CF, et al. Comprehensive genomic profiling in FIGHT-202 reveals the landscape of actionable alterations in advanced cholangiocarcinoma[J]. J Clin Oncol, 2019,37(15_suppl):4080. DOI: 10.1200/JCO.2019.37.15_suppl.4080.
[8]	Ghidini M, Pizzo C, Botticelli A, et al. Biliary tract cancer: current challenges and future prospects[J]. Cancer manag Res, 2018,11:379-388. DOI: 10.2147/CMAR.S157156. doi: 10.2147/CMAR.S157156 pmid: 30643463
[9]	Rizvi S, Borad MJ. The rise of the FGFR inhibitor in advanced biliary cancer: the next cover of time magazine?[J]. J Gastrointest Oncol, 2016,7(5):789-796. DOI: 10.21037/jgo.2016.08.12. doi: 10.21037/jgo.2016.08.12 pmid: 27747092
[10]	Rizvi S, Yamada D, Hirsova P, et al. A Hippo and fibroblast growth factor receptor autocrine pathway in cholangiocarcinoma[J]. J Biol Chem, 2016,291(15):8031-8047. DOI: 10.1074/jbc.M115.698472. doi: 10.1074/jbc.M115.698472 pmid: 26826125
[11]	Katoh M. Therapeutics targeting FGF signaling network in human diseases[J]. Trends Pharmacol Sci, 2016,37(12):1081-1096. DOI: 10.1016/j.tips.2016.10.003. doi: 10.1016/j.tips.2016.10.003 pmid: 27992319
[12]	Javle M, Lowery M, Shroff RT, et al. Phase Ⅱ study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma[J]. J Clin Oncol, 2018,36(3):276-282. DOI: 10.1200/jco.2017.75.5009. doi: 10.1200/JCO.2017.75.5009 pmid: 29182496
[13]	Vogel A, Sahai V, Hollebecque A, et al. FIGHT-202: a phase 2 study of pemigatinib in patients (Pts) with previously treated locally advanced or metastatic cholangiocarcinoma (CCA)[J]. Ann Oncol, 2019,30(suppl_5):v851-v934. DOI: 10.1093/annonc/mdz394.031.
[14]	Phase 3 study of BGJ398 (oral infigratinib) in first line cholangiocarcinoma with FGFR2 gene fusions/translocations[EB/OL]. [2020-04-13]. https://clinicaltrials.gov/ct2/show/NCT0377330-2?term=NCT03773302&draw=2&rank=1.
[15]	Mishra SK, Kumari N, Krishnani N. Molecular pathogenesis of gallbladder cancer: an update[J]. Mutat Res, 2019, 816-818:111674. DOI: 10.1016/j.mrfmmm.2019.111674. doi: 10.1016/j.mrfmmm.2019.111674 pmid: 31330366
[16]	Chong DQ, Zhu AX. The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets[J]. Oncotarget, 2016,7(29):46750-46767. DOI: 10.18632/oncotarget.8775.
[17]	A phase 2 trial of regorafenib as a single agent in advanced and metastatic biliary tract carcinoma/cholangiocarcinoma patients who have failed first-line chemotherapy[EB/OL]. [2019-01-30]. https://clinicaltrials.gov/ct2/show/NCT02053376?term=NCT02053376-&draw=2&rank=1.
[18]	Patel AK, Stoller RG, Rhee JC, et al. A phase Ⅱ trial of regorafenib as a single agent in patients with advanced and metastatic biliary tract carcinoma and first-line chemotherapy failure[J]. J Clin Oncol, 2015, 33(3_suppl):TPS498. DOI: 10.1200/jco.2015.33.3_suppl.tps498.
[19]	Sanchez-Gastaldo A, Gonzalez-Exposito R, Garcia-Carbonero R. Ramucirumab clinical development: an emerging role in gastrointes-tinal tumors[J]. Target Oncol, 2016,11(4):479-487. DOI: 10.1007/s11523-016-0419-8. doi: 10.1007/s11523-016-0419-8 pmid: 26887374
[20]	Ramucirumab in treating patients with advanced or metastatic, pre-viously treated biliary cancers that cannot be removed by surgery[EB/OL]. [2019-05-17]. https://clinicaltrials.gov/ct2/show/NCT025-20141?term=NCT02520141&draw=2&rank=1.
[21]	Mizrahi J, Javle MM, Xiao L, et al. A phase II study of ramuciru-mab for advanced, pre-treated biliary cancers[J]. J Clin Oncol. 2018,36(15_suppl):4081. DOI: 10.1200/JCO.2018.36.15_suppl.4081.
[22]	Kim JW, Lee KH, Kim J-W, et al. Phase Ⅰb study of binimetinib (MEK162) in combination with capecitabine in gemcitabine-pretreated advanced biliary tract cancer[J]. J Clin Oncol, 2018,36(15_suppl):4079. DOI: 10.1200/jco.2018.36.15_suppl.4079.
[23]	Bridgewater J, Lopes A, Beare S, et al. A phase 1b study of Selumetinib in combination with Cisplatin and Gemcitabine in advanced or metastatic biliary tract cancer: the ABC-04 study[J]. BMC Cancer, 2016,16:153. DOI: 10.1186/s12885-016-2174-8. pmid: 26912134
[24]	Jain A, Javle M. Molecular profiling of biliary tract cancer: a target rich disease[J]. J Gastrointest Oncol, 2016,7(5):797-803. DOI: 10.21037/jgo.2016.09.01. doi: 10.21037/jgo.2016.09.01 pmid: 27747093
[25]	Dang L, Yen K, Attar EC. IDH mutations in cancer and progress toward development of targeted therapeutics[J]. Ann Oncol, 2016,27(4):599-608. DOI: 10.1093/annonc/mdw013. pmid: 27005468
[26]	Lowery MA, Aboualfa GK, Burris HA, et al. Phase Ⅰ study of AG-120, an IDH1 mutant enzyme inhibitor: Results from the cholangiocarcinoma dose escalation and expansion cohorts[J]. J Clin Oncol, 2017,35(15_suppl):4015. DOI: 10.1200/JCO.2017.35.15_suppl.4015.
[27]	Bang YJ, Ueno M, Malka D, et al. Pembrolizumab (pembro) for advanced biliary adenocarcinoma: Results from the KEYNOTE-028 (KN028) and KEYNOTE-158 (KN158) basket studies[J]. J Clin Oncol, 2019,37(15_suppl):4079. DOI: 10.1200/JCO.2019.37.15_suppl.4079.
[28]	Ueno M, Ikeda M, Morizane C, et al. Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, phase 1 study[J]. Lancet Gastroenterol Hepatol, 2019,4(8):611-621. DOI: 10.1016/S2468-1253(19)30086-X. doi: 10.1016/S2468-1253(19)30086-X pmid: 31109808
[29]	Study of nivolumab in combination with gemcitabine/cisplatin or ipilimumab for patients with advanced unresectable biliary tract cancer[EB/OL]. [2020-01-13]. https://clinicaltrials.gov/ct2/show/NCT03101566?term=NCT03101566&draw=2&rank=1.
[30]	Hato SV, Khong A, de Vries IJ, et al. Molecular pathways: the immunogenic effects of platinum-based chemotherapeutics[J]. Clin Cancer Res, 2014,20(11):2831-2837. DOI: 10.1158/1078-0432.CCR-13-3141. doi: 10.1158/1078-0432.CCR-13-3141
[31]	Qin S, Chen Z, Liu Y, et al. A phase Ⅱ study of anti-PD-1 antibody camrelizumab plus FOLFOX4 or GEMOX systemic chemothe-rapy as first-line therapy for advanced hepatocellular carcinoma or biliary tract cancer[J]. J Clin Oncol, 2019,37(15_suppl):4074. DOI: 10.1200/jco.2019.37.15_suppl.4074.
[32]	Lind H, Gameiro SR, Jochems C, et al. Dual targeting of TGF-β and PD-L1 via a bifunctional anti-PD-L1/TGF-βRⅡ agent: status of preclinical and clinical advances[J]. J Immunother Cancer, 2020,8(1):e000433. DOI: 10.1136/jitc-2019-000433. pmid: 32079617
[33]	Yoo C, Oh DY, Choi HJ, et al. AB053. P-21. M7824 (MSB0011-359C), a bifunctional fusion protein targeting transforming growth factor β (TGF-β) and PD-L1, in Asian patients with pretreated biliary tract cancer (BTC): efficacy by BTC subtype[J]. Hepatobiliary Surg Nutr, 2019, 8(Suppl 1):AB053. DOI: 10.21037/hbsn.2019.AB053.
[34]	Arkenau HT, Martin-Liberal J, Calvo E, et al. Ramucirumab plus pembrolizumab in patients with previously treated advanced or metastatic biliary tract cancer: nonrandomized, open-label, phase Ⅰ trial (JVDF)[J]. Oncologist, 2018,23(12):1407-e136. DOI: 10.1634/theoncologist.2018-0044. doi: 10.1634/theoncologist.2018-0044 pmid: 29853658
[35]	Lin J, Shi W, Zhao S, et al. Lenvatinib plus checkpoint inhibitors in patients (pts) with advanced intrahepatic cholangiocarcinoma (ICC): preliminary data and correlation with next-generation sequencing[J]. J Clin Oncol, 2018,36(4_suppl):500. DOI: 10.1200/JCO.2018.36.4_suppl.500.