Progress in perioperative immunotherapy for locally advanced gastric cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WU Xiaolong ,  LI Ziyu

Department of Gastrointestinal Oncology Ⅰ, Peking University Cancer Hospital, Beijing 100142, P. R. China;

Corresponding?author：

LI Ziyu, Email: ziyu_li@hsc.pku.edu.cn

Keywords：

locally advanced gastric cancer; perioperative therapy; immune checkpoint inhibitor; non-operative management; immune-related adverse event

DOI：

10.7507/1007-9424.202604062

Video：

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The treatment strategy for locally advanced gastric cancer is at a critical juncture, transitioning from traditional perioperative chemotherapy to a paradigm of immuno-combination therapy. Low pathological complete response rate, high postoperative recurrence rate, treatment intolerances of some patients under neoadjuvant chemotherapy model are key points. In recent years, the successful application of immune checkpoint inhibitors in advanced gastric cancer has driven their shift into the perioperative setting. This article summarizes the latest clinical trial data on perioperative immunotherapy for locally advanced gastric cancer and integrates advances in both domestic and international research, and further explores precision treatment strategies based on molecular subtypes such as programmed death ligand 1, microsatellite instability-high/deficient mismatch repair, human epidermal growth factor receptor 2 and Claudin 18.2, as well as the prospects of “chemotherapy-free” and “surgery-free” approaches for microsatellite instability-high patients. The aim is to provide a comprehensive, evidence-based reference for safety challenges of perioperative immunotherapy within clinical practice and future research directions.

Citation： WU Xiaolong, LI Ziyu. Progress in perioperative immunotherapy for locally advanced gastric cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2026, 33(5): 623-628. doi: 10.7507/1007-9424.202604062 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. Zheng R, Zhang S, Zeng H, et al. Cancer incidence and mortality in China, 2016. J Natl Cancer Cent, 2022, 2(1): 1-9.
3. Thrift AP, Wenker TN, El-Serag HB. Global burden of gastric cancer: epidemiological trends, risk factors, screening and prevention. Nat Rev Clin Oncol, 2023, 20(5): 338-349.
4. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med, 2006, 355(1): 11-20.
5. Al-Batran SE, Homann N, Pauligk C, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet, 2019, 393(10184): 1948-1957.
6. Smyth EC, Nilsson M, Grabsch HI, et al. Gastric cancer. Lancet, 2020, 396(10251): 635-648.
7. Moore JL, Kumar S, Santaolalla A, et al. Effect of peri-operative chemotherapy regimen on survival in the treatment of locally advanced oesophago-gastric adenocarcinoma - a comparison of the FLOT and ‘MAGIC’ regimens. Eur J Cancer, 2022, 163: 180-188.
8. Kang YK, Yook JH, Park YK, et al. PRODIGY: a phase Ⅲ study of neoadjuvant docetaxel, oxaliplatin, and S-1 plus surgery and adjuvant S-1 versus surgery and adjuvant S-1 for resectable advanced gastric cancer. J Clin Oncol, 2021, 39(26): 2903-2913.
9. Zhang X, Liang H, Li Z, et al. Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial. Lancet Oncol, 2021, 22(8): 1081-1092.
10. Bang YJ, Kim YW, Yang HK, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet, 2012, 379(9813): 315-321.
11. Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med, 2007, 357(18): 1810-1820.
12. Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet, 2021, 398(10294): 27-40.
13. Xu J, Jiang H, Pan Y, et al. Sintilimab plus chemotherapy for unresectable gastric or gastroesophageal junction cancer: the ORIENT-16 randomized clinical trial. JAMA, 2023, 330(21): 2064-2074.
14. Qiu MZ, Oh DY, Kato K, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial. BMJ, 2024, 385: e078876. doi: 10.1136/bmj-2023-078876.
15. Rha SY, Oh DY, Ya?ez P, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol, 2023, 24(11): 1181-1195.
16. Shitara K, Moehler MH, Ajani JA, et al. Nivolumab (NIVO)+chemotherapy (chemo) vs chemo as first–line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 4 year (yr) follow-up of CheckMate 649. J Clin Oncol, 2024, 42, suppl 3. doi 10.1200/JCO.2024.42.3_suppl.306.
17. Janjigian YY, Al-Batran SE, Wainberg ZA, et al. Perioperative durvalumab in gastric and gastroesophageal junction cancer. N Engl J Med, 2025, 393(3): 217-230.
18. Shitara K, Rha SY, Wyrwicz LS, et al. Neoadjuvant and adjuvant pembrolizumab plus chemotherapy in locally advanced gastric or gastro-oesophageal cancer (KEYNOTE-585): an interim analysis of the multicentre, double-blind, randomised phase 3 study. Lancet Oncol, 2024, 25(2): 212-224.
19. André T, Tougeron D, Piessen G, et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in localized deficient mismatch repair/microsatellite instability-high gastric or esophagogastric junction adenocarcinoma: the GERCOR NEONIPIGA phase Ⅱ study. J Clin Oncol, 2023, 41(2): 255-265.
20. Raimondi A, Lonardi S, Murgioni S, et al. Tremelimumab and durvalumab as neoadjuvant or non-operative management strategy of patients with microsatellite instability-high resectable gastric or gastroesophageal junction adenocarcinoma: the INFINITY study by GONO. Ann Oncol, 2025, 36(3): 285-296.
21. Tabernero J, Al-Batran SE, Wainberg ZA, et al. Final overall survival (OS) and the association of pathological outcomes with event-free survival (EFS) in MATTERHORN: a randomised, phase Ⅲ study of durvalumab (D) plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in resectable gastric / gastroesophageal junction (G / GEJ) adenocarcinoma. Ann Oncol, 2025, 36, Suppl 2: S1623-S1624. doi: 10.1016/j.annonc.2025.09.096.
22. Pernomian LS, Teixeira MF, Araujo RL, et al. Perioperative immunotherapy in gastric cancer in the spotlight. World J Clin Oncol, 2025, 16(12): 110988. doi: 10.5306/wjco.v16.i12.110988.
23. Liu P, Chen J, Zhao L, et al. PD-1 blockade synergizes with oxaliplatin-based, but not cisplatin-based, chemotherapy of gastric cancer. Oncoimmunology, 2022, 11(1): 2093518. doi: 10.1080/2162402X.2022.2093518.
24. Omori R, Fujiwara Y, Tokunaga K, et al. Perioperative chemoimmunotherapy for patients with gastric or gastroesophageal junction cancer: a systematic review and meta-analysis. JNCI Cancer Spectr, 2026, 10(1): pkag003. doi: 10.1093/jncics/pkag003.
25. Li C, Tian Y, Zheng Y, 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 Clin Oncol, 2025, 43(4): 464-474.
26. Lorenzen S, G?tze TO, Thuss-Patience P, et al. Perioperative atezolizumab plus fluorouracil, leucovorin, oxaliplatin, and docetaxel for resectable esophagogastric cancer: interim results from the randomized, multicenter, phase Ⅱ/Ⅲ DANTE/IKF-s633 trial. J Clin Oncol, 2024, 42(4): 410-420.
27. Kang YK, Terashima M, Kim YW, et al. Adjuvant nivolumab plus chemotherapy versus placebo plus chemotherapy for stage Ⅲ gastric or gastro-oesophageal junction cancer after gastrectomy with D2 or more extensive lymph-node dissection (ATTRACTION-5): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol, 2024, 9(8): 705-717.
28. Lordick F, Mauer ME, Stocker G, et al. Adjuvant immunotherapy in patients with resected gastric and oesophagogastric junction cancer following preoperative chemotherapy with high risk for recurrence (ypN+ and/or R1): European Organisation of Research and Treatment of Cancer (EORTC) 1707 VESTIGE study. Ann Oncol, 2025, 36(2): 197-207.
29. Yuan SQ, Nie RC, Jin Y, et al. Perioperative toripalimab and chemotherapy in locally advanced gastric or gastro-esophageal junction cancer: a randomized phase 2 trial. Nat Med, 2024, 30(2): 552-559.
30. Nie RC, Yuan SQ, Ding Y, et al. Perioperative tislelizumab plus chemotherapy for locally advanced gastroesophageal junction adenocarcinoma (NEOSUMMIT-03): a prospective, nonrandomized, open-label, phase 2 trial. Signal Transduct Target Ther, 2025, 10(1): 60. doi: 10.1038/s41392-025-02160-8.
31. Alsina M, Villacampa G, de Andrea C, et al. A phase Ⅱ study of perioperative avelumab plus chemotherapy for patients with resectable gastric cancer or gastroesophageal junction cancer-the MONEO study. Clin Cancer Res, 2025, 31(14): 2890-2898.
32. Zhao L, Liu H, Yu J, et al. Efficacy and safety of neoadjuvant toripalimab plus chemotherapy in localized deficient mismatch repair/microsatellite instability-high gastric or esophagogastric junction adenocarcinoma (NICE): a multicentre, single-arm, exploratory phase 2 study. EClinicalMedicine, 2025, 87: 103421. doi: 10.1016/j.eclinm.2025.103421.
33. Peng Z, Zhang X, Liang H, et al. Atezolizumab and trastuzumab plus chemotherapy for ERBB2-positive locally advanced resectable gastric cancer: a randomized clinical trial. JAMA Oncol, 2025, 11(6): 619-624.
34. Stein A, Goekkurt E, Al-Batran SE, et al. Perioperative pembrolizumab, trastuzumab and FLOT in HER2-positive localized esophagogastric adenocarcinoma: a phase 2 trial. Nat Med, 2025, 31(12): 4197-4204.
35. Okemoto D, Nakayama I, Shitara K. Bridging paradigms and shaping the future of resectable gastric cancer: a narrative review of the post-MATTERHORN era. Gastroenterol Rep (Oxf), 2026, 14: goag010. doi: 10.1093/gastro/goag010.
36. 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 Clin Oncol, 2022, 40(32): 3750-3761.
37. Takahari D, Kawazoe A, Machida N, et al. Phase 2 study of trastuzumab deruxtecan in the neoadjuvant treatment for patients with HER2-positive gastric and gastroesophageal junction adenocarcinoma (EPOC2003). J Clin Oncol, 2022, 40(suppl 16): TPS4161. doi: 10.1200/JCO.2022.40.16_suppl.TPS4161.
38. Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet, 2023, 401(10389): 1655-1668.
39. Nakayama I, Qi C, Chen Y, et al. Claudin 18.2 as a novel therapeutic target. Nat Rev Clin Oncol, 2024, 21(5): 354-369.
40. Kelly RJ, Landon BV, Zaidi AH, et al. Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ⅰ b trial and ctDNA analyses. Nat Med, 2024, 30(4): 1023-1034.
41. Wang L, Sun M, Li J, et al. Intestinal subtype as a biomarker of response to neoadjuvant immunochemotherapy in locally advanced gastric adenocarcinoma: insights from a prospective phase Ⅱ trial. Clin Cancer Res, 2025, 31(1): 74-86.
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CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Progress in perioperative immunotherapy for locally advanced gastric cancer

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