Skip to main content

Advertisement

SpringerLink
Log in

Perioperative immune checkpoint inhibitor therapy for gastric and gastroesophageal junction cancers: a review of current approaches and future perspectives

  • Invited Review Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Metastatic gastric and gastroesophageal junction cancers have been treated with chemotherapy, but the landscape of cancer treatment is rapidly shifting towards immune-based therapies. As established by the CheckMate 649 and ATTRACTION-4 trials, combination therapy with fluorouracil, platinum, and nivolumab, an immune checkpoint inhibitor, is now recognized as the standard first-line chemotherapy for HER2-negative gastric and gastroesophageal junction cancer. The potential of immune checkpoint inhibitors extends beyond metastatic disease. For locally advanced gastric and gastroesophageal junction cancer, perioperative chemotherapy with gastrectomy has been regarded as the standard of care, especially in Western nations. Besides, the introduction of immune checkpoint inhibitors as neoadjuvant and adjuvant treatments is currently underway, indicating a significant paradigm shift in the treatment strategies. This review summarizes the clinical developments and future perspectives of immune checkpoint inhibitor therapy with or without chemotherapy as perioperative treatment for gastric, esophageal, and gastroesophageal junction cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. World Cancer research Fund International. Stomach cancer statistics. Available at https://www.wcrf.org/cancer-trends/stomach-cancer-statistics/. Accessed 6 Mar 2023

  2. Kang YK, Boku N, Satoh T et al (2017) Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 390:2461–2471

    Article  CAS  PubMed  Google Scholar 

  3. Janjigian YY, Shitara K, Moehler M et al (2021) 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 398:27–40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kang YK, Chen LT, Ryu MH et al (2022) Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 23:234–247

    Article  CAS  PubMed  Google Scholar 

  5. Cunningham D, Allum WH, Stenning SP et al (2006) Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355:11–20

    Article  CAS  PubMed  Google Scholar 

  6. Ychou M, Boige V, Pignon JP et al (2011) Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 29:1715–1721

    Article  CAS  PubMed  Google Scholar 

  7. Alderson D, Cunningham D, Nankivell M et al (2017) Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial. Lancet Oncol 18:1249–1260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Al-Batran SE, Homann N, Pauligk C et al (2019) 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 393:1948–1957

    Article  PubMed  Google Scholar 

  9. Macdonald JS, Smalley SR, Benedetti J et al (2001) Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345:725–730

    Article  CAS  PubMed  Google Scholar 

  10. Fuchs CS, Niedzwiecki D, Mamon HJ et al (2017) Adjuvant chemoradiotherapy with epirubicin, cisplatin, and fluorouracil compared with adjuvant chemoradiotherapy with fluorouracil and leucovorin after curative resection of gastric cancer: results from CALGB 80101 (alliance). J Clin Oncol 35:3671–3677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cats A, Jansen EPM, van Grieken NCT et al (2018) Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol 19:616–628

    Article  CAS  PubMed  Google Scholar 

  12. Lee J, Lim DH, Kim S et al (2012) Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial. J Clin Oncol 30:268–273

    Article  CAS  PubMed  Google Scholar 

  13. Park SH, Lim DH, Sohn TS et al (2021) A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial. Ann Oncol 32:368–374

    Article  CAS  PubMed  Google Scholar 

  14. Slagter AE, Jansen EPM, van Laarhoven HWM et al (2018) CRITICS-II: a multicentre randomised phase II trial of neo-adjuvant chemotherapy followed by surgery versus neo-adjuvant chemotherapy and subsequent chemoradiotherapy followed by surgery versus neo-adjuvant chemoradiotherapy followed by surgery in resectable gastric cancer. BMC Cancer 18:877

    Article  PubMed  PubMed Central  Google Scholar 

  15. Stahl M, Walz MK, Riera-Knorrenschild J et al (2017) Preoperative chemotherapy versus chemoradiotherapy in locally advanced adenocarcinomas of the oesophagogastric junction (POET): long-term results of a controlled randomised trial. Eur J Cancer 81:183–190

    Article  CAS  PubMed  Google Scholar 

  16. Tian Y, Wang J, Qiao X et al (2021) Long-term efficacy of neoadjuvant concurrent chemoradiotherapy for potentially resectable advanced siewert type II and III adenocarcinomas of the esophagogastric junction. Front Oncol 11:756440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Leong T, Smithers BM, Haustermans K et al (2017) TOPGEAR: a randomized, phase III trial of perioperative ECF chemotherapy with or without preoperative chemoradiation for resectable gastric cancer: interim results from an international, intergroup trial of the AGITG, TROG, EORTC and CCTG. Ann Surg Oncol 24:2252–2258

    Article  PubMed  Google Scholar 

  18. Lorenzen S, Biederstädt A, Ronellenfitsch U et al (2020) RACE-trial: neoadjuvant radiochemotherapy versus chemotherapy for patients with locally advanced, potentially resectable adenocarcinoma of the gastroesophageal junction—a randomized phase III joint study of the AIO. ARO and DGAV BMC Cancer 20:886

    Article  CAS  PubMed  Google Scholar 

  19. Lordick F, Carneiro F, Cascinu S et al (2022) Gastric cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol 33:1005–1020

    Article  CAS  PubMed  Google Scholar 

  20. Ajani JA, D’Amico TA, Bentrem DJ et al (2022) Gastric cancer, version 2.2022, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 20:167–192

    Article  CAS  PubMed  Google Scholar 

  21. Sasako M, Sakuramoto S, Katai H et al (2011) Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol 29:4387–4393

    Article  CAS  PubMed  Google Scholar 

  22. Yoshida K, Kodera Y, Kochi M et al (2019) Addition of docetaxel to oral fluoropyrimidine improves efficacy in patients with stage III gastric cancer: interim analysis of JACCRO GC-07, a randomized controlled trial. J Clin Oncol 37:1296–1304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yoshikawa T, Terashima M, Mizusawa J et al (2019) Four courses versus eight courses of adjuvant S-1 for patients with stage II gastric cancer (JCOG1104 [OPAS-1]): an open-label, phase 3, non-inferiority, randomised trial. Lancet Gastroenterol Hepatol 4:208–216

    Article  PubMed  Google Scholar 

  24. Bang YJ, Kim YW, Yang HK et al (2012) (2012) Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet 379:315–321

    Article  CAS  PubMed  Google Scholar 

  25. Japanese Gastric Cancer Association (2023) Japanese gastric cancer treatment guidelines 2021 (6th edition). Gastric Cancer 26:1–25

    Article  Google Scholar 

  26. Tsuburaya A, Mizusawa J, Tanaka Y et al (2014) Neoadjuvant chemotherapy with S-1 and cisplatin followed by D2 gastrectomy with para-aortic lymph node dissection for gastric cancer with extensive lymph node metastasis. Br J Surg 101:653–660

    Article  CAS  PubMed  Google Scholar 

  27. Iwasaki Y, Terashima M, Mizusawa J et al (2021) Gastrectomy with or without neoadjuvant S-1 plus cisplatin for type 4 or large type 3 gastric cancer (JCOG0501): an open-label, phase 3, randomized controlled trial. Gastric Cancer 24:492–502

    Article  CAS  PubMed  Google Scholar 

  28. Zhang X, Liang H, Li Z et al (2021) 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 22:1081–1092

    Article  CAS  PubMed  Google Scholar 

  29. Wang X, Li S, Xie T et al (2020) Early results of the randomized, multicenter, controlled evaluation of S-1 and oxaliplatin as neoadjuvant chemotherapy for Chinese advanced gastric cancer patients (RESONANCE Trial). J Clin Oncol 38(suppl):280

    Article  Google Scholar 

  30. Wang X, Li S, Sun Y et al (2021) The protocol of a prospective, multicenter, randomized, controlled phase III study evaluating different cycles of oxaliplatin combined with S-1 (SOX) as neoadjuvant chemotherapy for patients with locally advanced gastric cancer: RESONANCE-II trial. BMC Cancer 21:20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kang YK, Yook JH, Park YK et al (2021) 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 39:2903–2913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mizusawa J, Tokunaga M, Machida N et al (2022) Protocol digest of a phase III trial to evaluate the efficacy of preoperative chemotherapy with S-1 plus oxaliplatin followed by D2 gastrectomy with postoperative S-1 in locally advanced gastric cancer: Japan Clinical Oncology Group study JCOG1509 (NAGISA Trial). Jpn J Clin Oncol 53:168–173

    Article  Google Scholar 

  33. Kelsen DP, Ginsberg R, Pajak TF et al (1998) Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 339:1979–1984

    Article  CAS  PubMed  Google Scholar 

  34. Medical Research Council Oesophageal Cancer Working Group (2002) Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet 359:1727–1733

    Article  Google Scholar 

  35. van Hagen P, Hulshof MC, van Lanschot JJ et al (2012) Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 366:2074–2084

    Article  PubMed  Google Scholar 

  36. Klevebro F, Alexandersson von Döbeln G, Wang N et al (2016) A randomized clinical trial of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the oesophagus or gastro-oesophageal junction. Ann Oncol 27:660–667

    Article  CAS  PubMed  Google Scholar 

  37. Kelly RJ, Ajani JA, Kuzdzal J et al (2021) Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med 384:1191–1203

    Article  CAS  PubMed  Google Scholar 

  38. Obermannová R, Alsina M, Cervantes A et al (2022) ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol 33:992–1004

    Article  PubMed  Google Scholar 

  39. Kitagawa Y, Ishihara R, Ishikawa H et al (2023) Esophageal cancer practice guidelines 2022 edited by the Japan esophageal society: part 1. Esophagus. https://doi.org/10.1007/s10388-023-00993-2. (Epub ahead of print)

    Article  PubMed  PubMed Central  Google Scholar 

  40. Reynolds JV, Preston SR, O’Neill B et al (2023) Neo-AEGIS (neoadjuvant trial in adenocarcinoma of the esophagus and esophago-gastric junction international study): final primary outcome analysis. J Clin Oncol. https://doi.org/10.1200/JCO.2023.41.4_suppl.295

    Article  PubMed  PubMed Central  Google Scholar 

  41. Hoeppner J, Lordick F, Brunner T et al (2016) ESOPEC: prospective randomized controlled multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (NCT02509286). BMC Cancer 16:503

    Article  PubMed  PubMed Central  Google Scholar 

  42. Hasegawa H, Shitara K, Takiguchi S et al (2022) A multicenter, open-label, single-arm phase I trial of neoadjuvant nivolumab monotherapy for resectable gastric cancer. Gastric Cancer 25:619–628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Al-Batran SE, Lorenzen S, Thuss-Patience PC et al (2022) Surgical and pathological outcome, and pathological regression, in patients receiving perioperative atezolizumab in combination with FLOT chemotherapy versus FLOT alone for resectable esophagogastric adenocarcinoma: Interim results from DANTE, a randomized, multicenter, phase IIb trial of the FLOT-AIO German Gastric Cancer Group and Swiss SAKK. J Clin Oncol 40(suppl):4003–4003

    Article  Google Scholar 

  44. Zhu M, Chen C, Foster NR et al (2022) Pembrolizumab in combination with neoadjuvant chemoradiotherapy for patients with resectable adenocarcinoma of the gastroesophageal junction. Clin Cancer Res 28:3021–3031

    Article  CAS  PubMed  Google Scholar 

  45. Terashima M, Kim YW, Yeh TS et al (2017) ATTRACTION-05 (ONO-4538–38/BMS CA209844): a randomized, multicenter, double-blind, placebo-controlled Phase 3 study of Nivolumab (Nivo) in combination with adjuvant chemotherapy in pStage III gastric and esophagogastric junction(G/EGJ) cancer. Ann Oncol 28:v266–v267

    Article  Google Scholar 

  46. Ono Announces Results from Phase 3 Clinical Study Evaluating Opdivo in Combination with Chemotherapy as Adjuvant Treatment in Patients with Gastric Cancer and Esophagogastric Junction Cancer. Available at https://www.ono-pharma.com/en/news/20221223.html Accessed 9 Mar 2023

  47. Bang YJ, Van Cutsem E, Fuchs CS et al (2019) KEYNOTE-585: phase III study of perioperative chemotherapy with or without pembrolizumab for gastric cancer. Future Oncol 15:943–952

    Article  CAS  PubMed  Google Scholar 

  48. Janjigian YY, Van Cutsem E, Muro K et al (2021) MATTERHORN: efficacy and safety of neoadjuvant-adjuvant durvalumab and FLOT chemotherapy in resectable gastric and gastroesophageal junction cancer—a randomized, double-blind, placebo-controlled, phase 3 study. J Clin Oncol. https://doi.org/10.1200/JCO.2021.39.15_suppl.TPS4151

    Article  PubMed  PubMed Central  Google Scholar 

  49. Eads JR, Weitz M, Catalano PJ et al (2021) A phase II/III study of perioperative nivolumab and ipilimumab in patients (pts) with locoregional esophageal (E) and gastroesophageal junction (GEJ) adenocarcinoma: results of a safety run-in—a trial of the ECOG-ACRIN Cancer Research Group (EA2174). J Clin Oncol 39(suppl):4064–4064

    Article  Google Scholar 

  50. Kawazoe A, Fukuoka S, Nakamura Y et al (2020) 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. Lancet Oncol 21:1057–1065

    Article  CAS  PubMed  Google Scholar 

  51. Shitara K, Van Cutsem E, Bang YJ et al (2020) Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: the KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol 6:1571–1580

    Article  PubMed  Google Scholar 

  52. Smyth EC, Wotherspoon A, Peckitt C et al (2017) Mismatch repair deficiency, microsatellite instability, and survival: an exploratory analysis of the medical research council adjuvant gastric infusional chemotherapy(MAGIC) trial. JAMA Oncol 3:1197–1203

    Article  PubMed  Google Scholar 

  53. Choi YY, Kim H, Shin SJ et al (2018) Microsatellite instability and programmed cell death-ligand 1 expression in stage II/III gastric cancer: post hoc analysis of the CLASSIC randomized controlled study. Ann Surg 270:309–316

    Article  Google Scholar 

  54. Bajetta E, Floriani I, Di Bartolomeo M et al (2014) Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer. Ann Oncol 25:1373–1378

    Article  CAS  PubMed  Google Scholar 

  55. Pietrantonio F, Miceli R, Raimondi A et al (2019) Individual patient data meta-analysis of the value of microsatellite instability as a biomarker in gastric cancer. J Clin Oncol 37:3392–3400

    Article  PubMed  Google Scholar 

  56. André T, Tougeron D, Piessen G et al (2023) 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 41:255–265

    Article  PubMed  Google Scholar 

  57. Raimondi A, Palermo F, Prisciandaro M et al (2021) TremelImumab and durvalumab combination for the non-operative management (NOM) of microsatellite instability (MSI)-high resectable gastric or gastroesophageal junction cancer: the multicentre, single-arm, multi-cohort, phase II INFINITY study. Cancers (Basel) 13:2839

    Article  CAS  PubMed  Google Scholar 

  58. Chalabi M, Verschoor YL, van den Berg J et al (2022) Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: the NICHE-2 study. Ann Oncol 33(suppl 7):S808–S809

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan

    Daisuke Takahari & Izuma Nakayama

Authors
  1. Daisuke Takahari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Izuma Nakayama
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daisuke Takahari.

Ethics declarations

Conflicts of interest

Daisuke Takahari has received lecture fees from Taiho, Eli Lilly, Ono, Daiichi-Sankyo and BMS. Izuma Nakayama reports no conflicts of interest.

Research involves human and animal participants

This review article involves no studies of human or animal subjects performed by the author. In all studies, informed consent was obtained from all patients for inclusion in the respective studies.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Takahari, D., Nakayama, I. Perioperative immune checkpoint inhibitor therapy for gastric and gastroesophageal junction cancers: a review of current approaches and future perspectives. Int J Clin Oncol 28, 1431–1441 (2023). https://doi.org/10.1007/s10147-023-02388-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-023-02388-w

Keywords

Search

Navigation