HER2靶向药物及其联合治疗方案在胃及食管胃结合部腺癌治疗中的研究进展

国际肿瘤学杂志››2023,Vol. 50››Issue (12): 751-757.doi:10.3760/cma.j.cn371439-20230911-00141

HER2靶向药物及其联合治疗方案在胃及食管胃结合部腺癌治疗中的研究进展

邓莉莉¹^,², 段星宇³, 李保中⁴()

¹河南科技大学临床医学系，洛阳 471000
²河南省安阳市肿瘤医院肿瘤内科，安阳 455000
³新乡医学院附属郑州市第一人民医院骨科，郑州 450000
⁴河南省安阳市肿瘤医院外科，安阳 455000

收稿日期:2023-09-11修回日期:2023-10-16出版日期:2023-12-08发布日期:2024-01-16
通讯作者:李保中 E-mail:libaozhong99@126.com
基金资助:
安阳市重大科技专项(2022A02SF010)

Advances of anti-HER2 targeted drugs and combined therapeutic regimens for gastric and esophagogastic adenocarcinoma

Deng Lili¹^,², Duan Xingyu³, Li Baozhong⁴()

¹Department of Clinical Medicine， Henan University of Science and Technology， Luoyang 471000， China
²Department of Oncology， Anyang Tumor Hospital of Henan Province， Anyang 455000， China
³Department of Orthopedics， First People's Hospital of Zhengzhou Affiliated to Xinxiang Medical College， Zhengzhou 450000， China
⁴Department of Surgery， Anyang Tumor Hospital of Henan Province， Anyang 455000， China

Received:2023-09-11Revised:2023-10-16Online:2023-12-08Published:2024-01-16
Contact:Li Baozhong E-mail:libaozhong99@126.com
Supported by:
Major Science and Technology Project in Anyang(2022A02SF010)

摘要/Abstract

摘要：

人表皮生长因子受体2（HER2）过表达或扩增胃及食管胃结合部腺癌可从抗HER2治疗中显著获益。目前，除曲妥珠单抗、帕妥珠单抗等人源化单克隆抗体外，多种针对HER2的抗体偶联药（恩美曲妥珠单抗、维迪西妥单抗、德喜曲妥珠单抗、ARX788）及酪氨酸激酶抑制剂（拉帕替尼、阿法替尼、吡咯替尼），可作为单一疗法或联合疗法应用于晚期胃及食管胃结合部腺癌的治疗，已在临床研究中显示出良好疗效，改善了患者预后及生命质量。进一步研究新型HER2靶向药物及联合治疗方案在临床治疗中的疗效与安全性，有望为HER2阳性晚期胃及食管胃结合部腺癌患者的治疗提供更有效的策略。

关键词:胃肿瘤,腺癌,食管胃接合处,基因，erbB-2,分子靶向治疗

Abstract:

Patients with human epidermal growth factor receptor 2 （HER2） overexpression or amplification in gastric and esophagogastic adenocarcinoma can significantly benefit from anti-HER2 therapies. Presently， various humanized monoclonal antibodies such as trastuzumab and pertuzumab， alongside diverse anti-HER2 antibody drug conjugates （trastuzumab emtansine， disitamab vedotin， trastuzumab deruxtecan， ARX788）， and tyrosine kinase inhibitors （lapatinib， afatinib， pyrotinib）， are employed either as monotherapy or in combination settings for advanced gastric and esophagogastic adenocarcinoma. These therapeutic modalities have demonstrated promising clinical efficacy in clinical trials， thereby ameliorating patients' prognosis and enhancing life quality. Further exploration on the efficacy and safety of novel HER2-targeted agents and combined therapeutic regimens in clinical practice holds the promise of furnishing more efficacious strategies for treating HER2-positive advanced gastric and esophagogastic adenocarcinoma.

Key words:Stomach neoplasms,Adenocarcinoma,Esophagogastric junction,Genes， erbB-2,Molecular targeted therapy

邓莉莉, 段星宇, 李保中. HER2靶向药物及其联合治疗方案在胃及食管胃结合部腺癌治疗中的研究进展[J]. 国际肿瘤学杂志, 2023, 50(12): 751-757.

Deng Lili, Duan Xingyu, Li Baozhong. Advances of anti-HER2 targeted drugs and combined therapeutic regimens for gastric and esophagogastic adenocarcinoma[J]. Journal of International Oncology, 2023, 50(12): 751-757.

参考文献37

[1]	Joshi SS, Badgwell BD. Current treatment and recent progress in gastric cancer[J].CA Cancer J Clin,2021,71(3): 264-279. DOI:10.3322/caac.21657.
[2]	Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial[J].Lancet,2010,376(9742): 687-697. DOI:10.1016/S0140-6736(10)61121-X.
[3]	Jimenez-Fonseca P, Carmona-Bayonas A, Martinez-Torron A, et al. External validity of clinical trials with diverse trastuzumab-based chemotherapy regimens in advanced gastroesophageal adenocarcinoma: data from the AGAMENON-SEOM registry[J].Ther Adv Med Oncol,2021,13: 17588359211019672. DOI: 10.1177/1758 8359211019672.
[4]	Xu D, Zhang Z, Zhang S, et al. Efficacy of trastuzumab combined with SOX or IP chemotherapy regimen in the treatment of advanced gastric cancer[J].J BUON,2021,26(3): 932-939. pmid:34268956
[5]	Rivera F, Izquierdo-Manuel M, García-Alfonso P, et al. Perioperative trastuzumab, capecitabine and oxaliplatin in patients with HER2-positive resectable gastric or gastro-oesophageal junction adenocarcinoma: NEOHX phase Ⅱ trial[J].Eur J Cancer,2021,145: 158-167. DOI:10.1016/j.ejca.2020.12.005.
[6]	Jiang SY, Qin Y, Shi YK. A case of locally advanced gastric cancer treated with nivolumab, trastuzumab, plus chemotherapy in a neoadjuvant setting[J].Chin Med J (Engl),2019,132(11): 1370-1371. DOI:10.1097/CM9.0000000000000241.
[7]	Hofheinz RD, Hegewisch-Becker S, Kunzmann V, et al. Trastuzumab in combination with 5-fluorouracil, leucovorin, oxaliplatin and docetaxel as perioperative treatment for patients with human epidermal growth factor receptor 2-positive locally advanced esophagogastric adenocarcinoma: a phase Ⅱ trial of the Arbeitsgemeinschaft Internistische Onkologie Gastric Cancer Study Group[J].Int J Cancer,2021,149(6): 1322-1331. DOI:10.1002/ijc.33696.
[8]	Hofheinz RD, Merx K, Haag GM, et al. FLOT versus FLOT/trastuzumab/pertuzumab perioperative therapy of human epidermal growth factor receptor 2-positive resectable esophagogastric adenocarcinoma: a randomized phase Ⅱ trial of the AIO EGA study group[J].J Clin Oncol,2022,40(32): 3750-3761. DOI:10.1200/JCO.22.00380.
[9]	Horita Y, Nishino M, Sugimoto S, et al. Phase Ⅱ clinical trial of second-line weekly paclitaxel plus trastuzumab for patients with HER2-positive metastatic gastric cancer[J].Anticancer Drugs,2019,30(1): 98-104. DOI:10.1097/CAD.0000000000000691.
[10]	魏松之, 魏淑琴, 李铂. 新辅助用药帕妥珠单抗联合曲妥珠单抗在局部晚期、炎症性或早期her2阳性老年乳腺癌患者中有效性及安全性[J].中国老年学杂志,2023,43(1): 44-47. DOI:10.3969/j.issn.1005-9202.2023.01.011.
[11]	Tabernero J, Hoff PM, Shen L, et al. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study[J].Lancet Oncol,2018,19(10): 1372-1384. DOI:10.1016/S1470-2045(18)30481-9. pmid:30217672
[12]	Catenacci DVT, Kang YK, Yoon HH, et al. Margetuximab with retifanlimab as first-line therapy in HER2⁺/PD-L1⁺unresectable or metastatic gastroesophageal adenocarcinoma: MAHOGANY cohort A[J].ESMO Open,2022,7(5): 100563. DOI:10.1016/j.esmoop.2022.100563.
[13]	Weisser NE, Sanches M, Escobar-Cabrera E, et al. An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity[J].Nat Commun,2023,14(1): 1394. DOI:10.1038/s41467-023-37029-3. pmid:36914633
[14]	李越. 一项一线治疗晚期HER2阳性胃食管腺癌的研究[EB/OL]. [2021-10-29][2023-11-27]. http://www.chinadrugtrials.org.cn/index.html.
[15]	Xu J, Ying J, Liu R, et al. KN026 (anti-HER2 bispecific antibody) in patients with previously treated, advanced HER2-expressing gastric or gastroesophageal junction cancer[J].Eur J Cancer,2023,178: 1-12. DOI:10.1016/j.ejca.2022.10.004.
[16]	Shanghai JMT-Bio Inc. KN026 in combination with chemotherapy in the second line treatment of HER-2 positive advanced or metastatic gastric cancer[EB/OL]. [2022-06-22][2023-11-23]. https://clinicaltrials.gov/study/NCT05427383?cond=NCT05427383&rank=1.
[17]	Thuss-Patience PC, Shah MA, Ohtsu A, et al. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study[J].Lancet Oncol,2017,18(5): 640-653. DOI:10.1016/S1470-2045(17)30111-0. pmid:28343975
[18]	Chen Z, Yuan J, Xu Y, et al. From AVATAR mice to patients: RC48-ADC exerted promising efficacy in advanced gastric cancer with HER2 expression[J].Front Pharmacol,2021,12: 757994. DOI:10.3389/fphar.2021.757994.
[19]	关文龙, 王风华. 2023年CSCO胃癌诊疗指南更新解读: 转移性胃癌靶向治疗[J].实用肿瘤杂志,2023,38(4): 301-304. DOI:10.13267/j.cnki.syzlzz.2023.048.
[20]	Shitara K, Iwata H, Takahashi S, et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study[J].Lancet Oncol,2019,20(6): 827-836. DOI:10.1016/S1470-2045(19)30088-9. pmid:31047804
[21]	Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer[J].N Engl J Med,2020,382(25): 2419-2430. DOI:10.1056/NEJMoa2004413.
[22]	Van Cutsem E, di Bartolomeo M, Smyth E, et al. Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study[J].Lancet Oncol,2023,24(7): 744-756. DOI:10.1016/S1470-2045(23)00215-2. pmid:37329891
[23]	Pegram MD, Hamilton EP, Tan AR, et al. First-in-human, phase 1 dose-escalation study of biparatopic anti-HER2 antibody-drug conjugate MEDI4276 in patients with HER2-positive advanced breast or gastric cancer[J].Mol Cancer Ther,2021,20(8): 1442-1453. DOI:10.1158/1535-7163.MCT-20-0014. pmid:34045233
[24]	Zhang Y, Qiu MZ, Wang JF, et al. Phase 1 multicenter, dose-expansion study of ARX788 as monotherapy in HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma[J].Cell Rep Med,2022,3(11): 100814. DOI:10.1016/j.xcrm.2022.100814.
[25]	季燕萍. ARX788在HER2阳性晚期胃癌和胃食管连接部腺癌患者中的有效性及安全性研究[EB/OL]. [2021-07-12][2023-11-23]. http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml.
[26]	燕飞虎, 王燕, 冉浩南, 等. 紫杉醇联合拉帕替尼对晚期胃癌的疗效及外周血中FGF、FGFR和免疫功能的影响[J].临床和实验医学杂志,2019,18(8): 833-836. DOI:10.3969/j.issn.1671-4695.2019.08.014.
[27]	Smyth EC, Rowley S, Cafferty FH, et al. Safety and efficacy of the addition of lapatinib to perioperative chemotherapy for resectable HER2-positive gastroesophageal adenocarcinoma: a randomized phase 2 clinical trial[J].JAMA Oncol,2019,5(8): 1181-1187. DOI:10.1001/jamaoncol.2019.1179.
[28]	Nakata S, Fujita M, Nakanishi H. Efficacy of afatinib and lapatinib against HER2 gene-amplified trastuzumab-sensitive and -resistant human gastric cancer cells[J].Anticancer Res,2019,39(11): 5927-5932. DOI:10.21873/anticanres.13797.
[29]	Zarkavelis G, Samantas E, Koliou GA, et al. AGAPP: efficacy of first-line cisplatin, 5-fluorouracil with afatinib in inoperable gastric and gastroesophageal junction carcinomas. A Hellenic Cooperative Oncology Group study[J].Acta Oncol,2021,60(6): 785-793. DOI:10.1080/0284186X.2021.1912822.
[30]	Li X, Gu X, Xu J, et al. Sustained clinical benefit of pyrotinib combined with capecitabine rescue therapy after trastuzumab resistance in HER2-positive advanced gastric cancer: a case report[J].Onco Targets Ther,2021,14: 3983-3989. DOI:10.2147/OTT.S310421.
[31]	Ma F, Li Q, Chen S, et al. Phase Ⅰ study and biomarker analysis of pyrotinib, a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor, in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer[J].J Clin Oncol,2017,35(27): 3105-3112. DOI:10.1200/JCO.2016.69.6179.
[32]	Liu D, Kou F, Gong J, et al. Pyrotinib alone or in combination with docetaxel in refractory HER2-positive gastric cancer: a dose-escalation phase Ⅰ study[J].Cancer Med,2023,12(9): 10704-10714. DOI:10.1002/cam4.5830.
[33]	Kim TY, Han HS, Lee KW, et al. A phase Ⅰ/Ⅱ study of poziotinib combined with paclitaxel and trastuzumab in patients with HER2-positive advanced gastric cancer[J].Gastric Cancer,2019,22(6): 1206-1214. DOI:10.1007/s10120-019-00958-4.
[34]	Kulukian A, Lee P, Taylor J, et al. Preclinical activity of HER2-selective tyrosine kinase inhibitor tucatinib as a single agent or in combination with trastuzumab or docetaxel in solid tumor models[J].Mol Cancer Ther,2020,19(4): 976-987. DOI:10.1158/1535-7163.MCT-19-0873. pmid:32241871
[35]	Hamzehlou S, Momeny M, Zandi Z, et al. Anti-tumor activity of neratinib, a pan-HER inhibitor, in gastric adenocarcinoma cells[J].Eur J Pharmacol,2019,863: 172705. DOI:10.1016/j.ejphar.2019.172705.
[36]	Alsina M, Arrazubi V, Diez M, et al. Current developments in gastric cancer: from molecular profiling to treatment strategy[J].Nat Rev Gastroenterol Hepatol,2023,20(3): 155-170. DOI:10.1038/s41575-022-00703-w.
[37]	Janjigian YY, Kawazoe A, Yañez P, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer[J].Nature,2021,600(7890): 727-730. DOI:10.1038/s41586-021-04161-3.