Research progress on targeted therapy for advanced gastric cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

HUANG Qiyue ¹ ,  GOU Hongfeng ²

1. Department of Oncology, Chengdu Sixth People’s Hospital, Chengdu 610041, P. R. China;
2. Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;

Corresponding?author：

GOU Hongfeng, Email: gouhongfeng1977@wchscu.cn

Keywords：

gastric cancer; targeted therapy; human epidermal growth factor receptor 2; Claudin 18.2; fibroblast growth factor receptor 2b

DOI：

10.7507/1007-9424.202604033

Video：

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Objective To systematically review the current clinical research status of major therapeutic targets and research advances in emerging targets for targeted therapy in advanced gastric cancer, so as to provide a reference for clinical precision therapy. Method The key studies on major therapeutic targets for targeted therapy are reviewed, including HER2 (human epidermal growth factor receptor 2), VEGFR2 (vascular endothelial growth factor receptor 2), Claudin 18.2, FGFR2b (fibroblast growth factor receptor 2b), DKK1 (Dickkopf-related protein 1), and MET (mesenchymal to epithelial transition) factor. Results Clinical research and application of anti-HER2 agents have been well established, and such agents have been utilized throughout the entire course from the first-line to later-line therapy. VEGFR2 inhibitors have been positioned as core treatments in the second-line and subsequent-line settings. The emergence of targeted therapy against Claudin 18.2 has provided the new first-line option for patients with HER2-negative advanced gastric cancer. Investigations into agents targeting targets, including FGFR2b, DKK1, and MET, have been continuously intensified. Conclusions Currently, survival of patients with advanced gastric cancer can be improved by targeted therapy. However, several challenges remain to be addressed, including heterogeneous target expression, complex resistance mechanisms, and uncertainty regarding the optimal treatment strategy. Further investigations are warranted in dynamic monitoring and standardization of target detection, clarification of resistance mechanisms and optimization of combination strategies, as well as sequencing of therapeutic agents and individualized treatment selection.

Citation： HUANG Qiyue, GOU Hongfeng. Research progress on targeted therapy for advanced gastric cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2026, 33(5): 654-663. doi: 10.7507/1007-9424.202604033 Copy

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1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
2. Han B, Zheng R, Zeng H, et al. Cancer incidence and mortality in China, 2022. J Natl Cancer Cent, 2024, 4(1): 47-53.
3. 赫捷, 陳萬青, 李兆申, 等. 中國胃癌篩查與早診早治指南(2022, 北京). 中華腫瘤雜志, 2022, 44(7): 634-666.
4. 中國臨床腫瘤學會指南工作委員會. 中國臨床腫瘤學會(CSCO)胃癌診療指南2025. 北京: 人民衛生出版社, 2025.
5. Lordick F, Carneiro F, Cascinu S, et al. Gastric cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol, 2022, 33(10): 1005-1020.
6. 卓萌, 韓婷, 肖秀英, 等. 胃癌新靶點的治療進展. 中華胃腸外科雜志, 2026, 29(2): 220-227.
7. Bartley AN, Washington MK, Colasacco C, et al. HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: guideline from the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. J Clin Oncol, 2017, 35(4): 446-464.
8. 《胃癌HER2檢測指南(2016版)》專家組. 胃癌HER2檢測指南(2016版). 中華病理學雜志, 2016, 45(8): 528-532.
9. 中國抗癌協會胃癌專業委員會. 胃癌抗HER2治療中國專家共識(2024年版). 中國腫瘤臨床, 2024, 51(23): 1189-1205.
10. 中國抗癌協會胃癌專業委員會, 中國抗癌協會腫瘤內鏡學專業委員會. 胃癌胃鏡活檢標本HER-2檢測中國專家共識(2023版). 中國腫瘤臨床, 2023, 50(19): 973-982.
11. 《胃癌Claudin 18.2臨床檢測專家共識(2025版)》專家委員會. 胃癌Claudin 18.2臨床檢測專家共識(2025版). 中華病理學雜志, 2025, 54(7): 718-725.
12. Lee HS. Spatial and temporal tumor heterogeneity in gastric cancer: discordance of predictive biomarkers. J Gastric Cancer, 2025, 25(1): 192-209.
13. Seo S, Ryu MH, Park YS, et al. Loss of HER2 positivity after anti-HER2 chemotherapy in HER2-positive gastric cancer patients: results of the GASTric cancer HER2 reassessment study 3 (GASTHER3). Gastric Cancer, 2019, 22(3): 527-535.
14. Hu HH, Wang SQ, Zhao H, et al. HER2+ advanced gastric cancer: current state and opportunities (Review). Int J Oncol, 2024, 64(4): 36. doi: 10.3892/ijo.2024.5624.
15. Blangé D, Stroes CI, Derks S, et al. Resistance mechanisms to HER2-targeted therapy in gastroesophageal adenocarcinoma: a systematic review. Cancer Treat Rev, 2022, 108: 102418. doi: 10.1016/j.ctrv.2022.102418.
16. Bang Y, 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 Ⅲ, open-label, randomised controlled trial. Lancet, 2010, 376(9742): 687-697.
17. Shitara K, Doi T, Bang YJ, et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med, 2020, 382(25): 2419-2430.
18. Shitara K, Van Cutsem E, Gümü? M, et al. Trastuzumab deruxtecan or ramucirumab plus paclitaxel in gastric cancer. N Engl J Med, 2025, 393(4): 336-348.
19. Janjigian YY, Smyth E, Shen L, et al. DESTINY-Gastric05 phase Ⅲ trial of first-line trastuzumab deruxtecan, chemotherapy, and pembrolizumab in HER2-positive gastric or gastroesophageal junction cancer. ESMO Gastrointest Oncol, 2026, 111: 00294. doi: 10.1016/j.esmogo.2026.100294.
20. Peng Z, Liu T, Wei J, et al. Efficacy and safety of a novel anti-HER2 therapeutic antibody RC48 in patients with HER2-overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: a single-arm phase Ⅱ study. Cancer Commun (Lond), 2021, 41(11): 1173-1182.
21. Li N, Qiu M, Zhang Y, et al. A randomized phase Ⅱ study of HLX22 plus trastuzumab biosimilar HLX02 and XELOX as first-line therapy for HER2-positive advanced gastric cancer. Cell Rep Med, 2024, 5(10): 101855. doi: 10.1016/j.xcrm.2024.101855.
22. Elimova E, Ajani J, Burris H, et al. Zanidatamab plus chemotherapy as first-line treatment for patients with HER2-positive advanced gastro-oesophageal adenocarcinoma: primary results of a multicentre, single-arm, phase 2 study. Lancet Oncol, 2025, 26(7): 847-859.
23. Lee KW, Bai LY, Jung M, et al. Phase Ⅰ b/Ⅱ study of zanidatamab in combination with tislelizumab and chemotherapy in first-line HER2-positive gastric/gastroesophageal junction adenocarcinoma. Clin Cancer Res, 2026, 32(2): 312-323.
24. Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet, 2023, 402(10418): 2197-2208.
25. Shen L, Peng Z, Li C, et al. Disitamab vedotin (DV) plus toripalimab (Tor) and chemotherapy (C)/trastuzumab (Tra) as first-line (1L) treatment of patients (pts) with HER2-expressing locally advanced or metastatic (la/m) gastric cancer. J Clin Oncol, 2025, 43(17_suppl): LBA4012. doi: 10.1200/JCO.2025.43.17_suppl.LBA4012.
26. Xu RH, Gomes DBD, Chen JS, et al. ARTEMIDE-Gastric01: a phase 3 randomized study of rilvegostomig with fluoropyrimidine and trastuzumab deruxtecan (T-DXd) as first-line (1L) treatment for locally advanced or metastatic HER2-positive gastric or gastroesophageal junction cancer (GC/GEJC). J Clin Oncol, 2025, 43(16_suppl): TPS4204. doi: 10.1200/JCO.2025.43.16_suppl.TPS4204.
27. Park SR, Park YS, Ryu MH, et al. Extra-gain of HER2-positive cases through HER2 reassessment in primary and metastatic sites in advanced gastric cancer with initially HER2-negative primary tumours: results of GASTric cancer HER2 reassessment study 1 (GASTHER1). Eur J Cancer, 2016, 53: 42-50.
28. Shao Q, Deng J, Wu H, et al. HER2-positive gastric cancer: from targeted therapy to CAR-T cell therapy. Front Immunol, 2025, 16: 1560280. doi: 10.3389/fimmu.2025.1560280.
29. Cao Y, Langer R, Ferrara N. Targeting angiogenesis in oncology, ophthalmology and beyond. Nat Rev Drug Discov, 2023, 22(6): 476-495.
30. 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. Lancet, 2014, 383(9911): 31-39.
31. 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. Lancet Oncol, 2014, 15(11): 1224-1235.
32. Li J, Qin S, Xu J, et al. Randomized, double-blind, placebo-controlled phase Ⅲ trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol, 2016, 34(13): 1448-1454.
33. Bang YJ, Kim ST, Kang YK et al. Rivoceranib versus placebo in patients with advanced gastric or gastroesophageal junction cancer refractory to at least two lines of chemotherapy (ANGEL): a randomized, double-blind, phase 3 trial. Lancet Oncol, 2022, 23(1): 117-128.
34. Wang F, Shen L, Guo W, et al. Fruquintinib plus paclitaxel versus placebo plus paclitaxel for gastric or gastroesophageal junction adenocarcinoma: the randomized phase 3 FRUTIGA trial. Nat Med, 2024, 30(8): 2189-2198.
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Research progress on targeted therapy for advanced gastric cancer

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