抗血管生成药物在食管胃结合部腺癌及胃癌治疗中的研究进展

doi:10.3760/cma.j.cn371439-20251231-00089

摘要/Abstract

摘要：

食管胃结合部腺癌（AEG）及胃癌是全球常见的恶性肿瘤，新生血管生成是肿瘤进展的关键机制。目前，抗血管生成治疗已成为AEG及胃癌治疗的重要策略。抗血管生成药物主要包括单克隆抗体（如贝伐珠单抗和雷莫芦单抗）和小分子酪氨酸激酶抑制剂（如阿帕替尼、呋喹替尼、瑞戈非尼、仑伐替尼、安罗替尼、索拉非尼、卡博替尼），可作为单药或联合用药应用于AEG及胃癌的多线、新辅助或转换维持治疗，显示出一定的生存获益。深入探讨抗血管生成药物在AEG及胃癌治疗中的研究进展，可为优化临床治疗策略提供参考。

关键词: 胃肿瘤, 腺癌, 食管胃接合处, 血管生成抑制剂

Abstract:

Adenocarcinoma of the esophagogastric junction （AEG） and gastric cancer are common malignant tumors worldwide. Angiogenesis is a key mechanism in tumor development. Currently，anti-angiogenic therapy has become an important strategy for the treatment of AEG and gastric cancer. Anti-angiogenic drugs mainly include monoclonal antibodies （such as bevacizumab and ramucirumab） and small molecule tyrosine kinase inhibitors （such as apatinib，fruquintinib，regorafenib，lenvatinib，anlotinib，sorafenib，and cabozantinib），which can be used as single drugs or in combination for multi-line，neoadjuvant or conversion maintenance treatment of AEG and gastric cancer，and have shown certain survival benefits. An in-depth exploration of the research progress of anti-angiogenic drugs in the treatment of AEG and gastric cancer can provide references for optimizing clinical treatment strategies.

Key words: Stomach neoplasms, Adenocarcinoma, Esophagogastric junction, Angiogenesis inhibitors

孙洁, 刘志强, 李保中. 抗血管生成药物在食管胃结合部腺癌及胃癌治疗中的研究进展[J]. 国际肿瘤学杂志, 2026, 53(9): 559-565.

Sun Jie, Liu Zhiqiang, Li Baozhong. Research progress of anti-angiogenic agents in the treatment of adenocarcinoma of the esophagogastric junction and gastric cancer[J]. Journal of International Oncology, 2026, 53(9): 559-565.

参考文献 42

[1]	Arnold M, Ferlay J, van Berge Henegouwen MI, et al. Global burden of oesophageal and gastric cancer by histology and subsite in 2018[J]. Gut, 2020, 69(9): 1564-1571. DOI: 10.1136/gutjnl-2020-321600.
[2]	Cao YH, Langer R, Ferrara N. Targeting angiogenesis in oncology, ophthalmology and beyond[J]. Nat Rev Drug Discov, 2023, 22(6): 476-495. DOI: 10.1038/s41573-023-00671-z.
[3]	Ohtsu A, Shah MA, Van Cutsem E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase Ⅲ study[J]. J Clin Oncol, 2011, 29(30): 3968-3976. DOI: 10.1200/JCO.2011.36.2236.
[4]	Shen L, Li J, Xu J, et al. Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase Ⅲ study (AVATAR study)[J]. Gastric Cancer, 2015, 18(1): 168-176. DOI: 10.1007/s10120-014-0351-5.
[5]	舒国亮, 侯湘德, 黄邵斌. 贝伐珠单抗联合FOLFOX化疗方案治疗晚期胃癌的临床疗效及其安全性[J]. 临床合理用药杂志, 2022, 15(33): 70-73. DOI: 10.15887/j.cnki.13-1389/r.2022.33.019.
[6]	Singh H, Lowder KE, Kapner K, et al. Clinical outcomes and ctDNA correlates for CAPOX BETR: a phase Ⅱ trial of capecitabine, oxaliplatin, bevacizumab, trastuzumab in previously untreated advanced HER2⁺ gastroesophageal adenocarcinoma[J]. Nat Commun, 2024, 15(1): 6833. DOI: 10.1038/s41467-024-51271-3.
[7]	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.
[8]	Yin B, Luo W. Efficacy and safety of neoadjuvant bevacizumab plus chemotherapy in locally advanced gastric cancer patients: a retrospective, comparative study[J]. World J Surg Oncol, 2025, 23(1): 26. DOI: 10.1186/s12957-024-03624-x.
[9]	Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial[J]. Lancet, 2014, 383(9911): 31-39. DOI: 10.1016/S0140-6736(13)61719-5.
[10]	Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial[J]. Lancet Oncol, 2014, 15(11): 1224-1235. DOI: 10.1016/S1470-2045(14)70420-6.
[11]	Xu RH, Zhang Y, Pan H, et al. Efficacy and safety of weekly paclitaxel with or without ramucirumab as second-line therapy for the treatment of advanced gastric or gastroesophageal junction adenocarcinoma (RAINBOW-Asia): a randomised, multicentre, double-blind, phase 3 trial[J]. Lancet Gastroenterol Hepatol, 2021, 6(12): 1015-1024. DOI: 10.1016/S2468-1253(21)00313-7.
[12]	Kim CG, Jung M, Kim HS, et al. Trastuzumab combined with ramucirumab and paclitaxel in patients with previously treated human epidermal growth factor receptor 2-positive advanced gastric or gastroesophageal junction cancer[J]. J Clin Oncol, 2023, 41(27): 4394-4405. DOI: 10.1200/JCO.22.02122.
[13]	Sasaki A, Kawazoe A, Eto T, et al. Improved efficacy of taxanes and ramucirumab combination chemotherapy after exposure to anti-PD-1 therapy in advanced gastric cancer[J]. ESMO Open, 2020, 4(Suppl 2): e000775. DOI: 10.1136/esmoopen-2020-000775.
[14]	Nakajima TE, Kadowaki S, Minashi K, et al. Multicenter phase Ⅰ/Ⅱ study of nivolumab combined with paclitaxel plus ramucirumab as second-line treatment in patients with advanced gastric cancer[J]. Clin Cancer Res, 2021, 27(4): 1029-1036. DOI: 10.1158/1078-0432.CCR-20-3559.
[15]	Thuss-Patience P, Högner A, Goekkurt E, et al. Ramucirumab, avelumab, and paclitaxel as second-line treatment in esophagogastric adenocarcinoma: the phase 2 RAP (AIO-STO-0218) nonrandomized controlled trial[J]. JAMA Netw Open, 2024, 7(1): e2352830. DOI: 10.1001/jamanetworkopen.2023.52830.
[16]	Kawazoe A, Ando T, Hosaka H, et al. Safety and activity of trifluridine/tipiracil and ramucirumab in previously treated advanced gastric cancer: an open-label, single-arm, phase 2 trial[J]. Lancet Gastroenterol Hepatol, 2021, 6(3): 209-217. DOI: 10.1016/S2468-1253(20)30396-4.
[17]	Kim DW, Kim RD, Jimenez MM, et al. A phase Ⅱ study of trifluridine/tipiracil in combination with ramucirumab in advanced, refractory gastric, or gastroesophageal junction adenocarcinomas[J]. Oncologist, 2025, 30(12): oyaf303. DOI: 10.1093/oncolo/oyaf303.
[18]	Sakai D, Kadowaki S, Kawabata R, et al. Randomized phase Ⅲ trial of ramucirumab beyond progression plus irinotecan in patients with ramucirumab-refractory advanced gastric cancer: RINDBeRG trial[J]. J Clin Oncol, 2025, 43(19): 2196-2207. DOI: 10.1200/JCO.24.01119.
[19]	Li J, Qin S, Wen L, et al. Safety and efficacy of apatinib in patients with advanced gastric or gastroesophageal junction adeno-carcinoma after the failure of two or more lines of chemotherapy (AHEAD): a prospective, single-arm, multicenter, phase Ⅳ study[J]. BMC Med, 2023, 21(1): 173. DOI: 10.1186/s12916-023-02841-7.
[20]	Peng Z, Wei J, Wang F, et al. Camrelizumab combined with chemotherapy followed by camrelizumab plus apatinib as first-line therapy for advanced gastric or gastroesophageal junction adenocarcinoma[J]. Clin Cancer Res, 2021, 27(11): 3069-3078. DOI: 10.1158/1078-0432.CCR-20-4691.
[21]	Chen X, Xu H, Chen X, et al. First-line camrelizumab (a PD-1 inhibitor) plus apatinib (an VEGFR-2 inhibitor) and chemotherapy for advanced gastric cancer (SPACE): a phase 1 study[J]. Signal Transduct Target Ther, 2024, 9(1): 73. DOI: 10.1038/s41392-024-01773-9.
[22]	Wang YK, Lu JL, Chong XY, et al. PD-1 antibody camrelizumab plus apatinib and SOX as first-line treatment in patients with AFP-producing gastric or gastro-esophageal junction adenocarcinoma (CAP 06): a multi-center, single-arm, phase 2 trial[J]. Signal Transduct Target Ther, 2025, 10(1): 100. DOI: 10.1038/s41392-025-02193-z.
[23]	蓝煜, 王风华. 2024晚期胃癌诊疗指南更新对比与梳理: CSCO、NCCN和ESMO[J]. 中国癌症杂志, 2025, 35(2): 219-227. DOI: 10.19401/j.cnki.1007-3639.2025.02.009.
[24]	Lin JX, Xu YC, Lin W, et al. Effectiveness and safety of apatinib plus chemotherapy as neoadjuvant treatment for locally advanced gastric cancer: a nonrandomized controlled trial[J]. JAMA Netw Open, 2021, 4(7): e2116240. DOI: 10.1001/jamanetworkopen.2021.16240.
[25]	Tang Z, Wang Y, Yu Y, et al. Neoadjuvant apatinib combined with oxaliplatin and capecitabine in patients with locally advanced adenocarcinoma of stomach or gastroesophageal junction: a single-arm, open-label, phase 2 trial[J]. BMC Med, 2022, 20(1): 107. DOI: 10.1186/s12916-022-02309-0.
[26]	Li C, Tian YT, Zheng YN, et al. Pathologic response of phase Ⅲ study: perioperative camrelizumab plus rivoceranib and chemotherapy versus chemotherapy for locally advanced gastric cancer (DRAGON Ⅳ/CAP 05)[J]. J Clin Oncol, 2025, 43(4): 464-474. DOI: 10.1200/JCO.24.00795.
[27]	Lin JX, Tang YH, Zheng HL, et al. Neoadjuvant camrelizumab and apatinib combined with chemotherapy versus chemotherapy alone for locally advanced gastric cancer: a multicenter randomized phase 2 trial[J]. Nat Commun, 2024, 15(1): 41. DOI: 10.1038/s41467-023-44309-5.
[28]	Zhang Y, Wang ZX, Shen L, et al. A phase Ⅰb/Ⅱ study of fruquintinib in combination with paclitaxel as the second-line therapy for advanced gastric cancer[J]. Cancer Commun (Lond), 2023, 43(1): 150-153. DOI: 10.1002/cac2.12379.
[29]	Wang F, Shen L, Guo WJ, et al. Fruquintinib plus paclitaxel versus placebo plus paclitaxel for gastric or gastroesophageal junction adenocarcinoma: the randomized phase 3 FRUTIGA trial[J]. Nat Med, 2024, 30(8): 2189-2198. DOI: 10.1038/s41591-024-02989-6.
[30]	林青雨, 戴伟钢, 李引, 等. 中国临床肿瘤学会胃癌诊疗指南(2025版)更新要点解读[J]. 消化肿瘤杂志(电子版), 2025, 17(3): 299-307. DOI: 10.3969/j.issn.1674-7402.2025.03.004.
[31]	Meng XY, Yang D, Liu YL, et al. Fruquintinib and sintilimab plus SOX as perioperative therapy for locally resectable advanced gastric/gastroesophageal junction adenocarcinoma: study protocol for a prospective, single-arm, phase Ⅱ clinical trial[J]. Front Immunol, 2025, 16: 1638316. DOI: 10.3389/fimmu.2025.1638316.
[32]	Pavlakis N, Shitara K, Sjoquist K, et al. INTEGRATE Ⅱa phase Ⅲ study: regorafenib for refractory advanced gastric cancer[J]. J Clin Oncol, 2025, 43(4): 453-463. DOI: 10.1200/JCO.24.00055.
[33]	Samalin E, Evesque L, Turpin A, et al. Regorafenib combined with irinotecan as second-line treatment in metastatic gastro-oesophageal adenocarcinomas: results of PRODIGE 58-UCGI35-REGIRI unicancer randomised phase Ⅱ study[J]. ESMO Open, 2025, 10(5): 105096. DOI: 10.1016/j.esmoop.2025.105096.
[34]	Cytryn SL, Moy RH, Cowzer D, et al. First-line regorafenib with nivolumab and chemotherapy in advanced oesophageal, gastric, or gastro-oesophageal junction cancer in the USA: a single-arm, single-centre, phase 2 trial[J]. Lancet Oncol, 2023, 24(10): 1073-1082. DOI: 10.1016/S1470-2045(23)00358-3.
[35]	Kawazoe A, Fukuoka S, Nakamura Y, et al. Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial[J]. Lancet Oncol, 2020, 21(8): 1057-1065. DOI: 10.1016/S1470-2045(20)30271-0.
[36]	Zhou CF, Jiang JL, Guo LT, et al. Lenvatinib plus paclitaxel as second-line therapy for advanced gastric cancer patients: a dose escalation exploratory study[J]. Adv Sci (Weinh), 2025, 12(40): e06678. DOI: 10.1002/advs.202506678.
[37]	Shitara K, Lorenzen S, Li J, et al. Lenvatinib plus pembrolizumab and chemotherapy versus chemotherapy in advanced metastatic gastroesophageal adenocarcinoma: the phase Ⅲ, randomized LEAP-015 study[J]. J Clin Oncol, 2025, 43(22): 2502-2514. DOI: 10.1200/JCO-25-00748.
[38]	Jiang M, Zhang CT, Hu YB, et al. Anlotinib combined with toripalimab as second-line therapy for advanced, relapsed gastric or gastroesophageal junction carcinoma[J]. Oncologist, 2022, 27(11): e856-e869. DOI: 10.1093/oncolo/oyac136.
[39]	Liu K, Qin BD, Chen SQ, et al. Anlotinib plus toripalimab as a first-line treatment in patients with advanced gastric cancer and performance status 2: the phase Ⅱ APICAL-GC trial[J]. Nat Commun, 2025, 16(1): 5069. DOI: 10.1038/s41467-025-60317-z.
[40]	Bie LY, Wei C, Luo SX, et al. Benmelstobart plus anlotinib and chemotherapy in HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma: a phase 2 study[J]. Cell Rep Med, 2025, 6(6): 102145. DOI: 10.1016/j.xcrm.2025.102145.
[41]	Ryu MH, Lee KH, Shen L, et al. Randomized phase Ⅱ study of capecitabine plus cisplatin with or without sorafenib in patients with metastatic gastric cancer (STARGATE)[J]. Cancer Med, 2023, 12(7): 7784-7794. DOI: 10.1002/cam4.5536.
[42]	Dayyani F, Chao J, Lee FC, et al. A phase Ⅱ study of cabozantinib and pembrolizumab in advanced gastric/gastroesophageal adenocarcinomas resistant or refractory to immune checkpoint inhibitors[J]. Oncologist, 2024, 29(8): 721-e1088. DOI: 10.1093/oncolo/oyae117.