Vol 72, No 5 (2022)
Review paper
Published online: 2022-08-26

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Immunotherapeutics and other anticancer agents in the management of advanced gastric cancer

Kajetan Kiełbowski1, Estera Bakinowska1, Przemysław Dymek1, Sandra Sienkiewicz1, Tomasz Błaszkowski1, Maciej Romanowski1
Nowotwory. Journal of Oncology 2022;72(5):308-318.


Advanced gastric cancer (AGC) is characterized by high mortality. The survival is estimated as 14.2 months. The treat­ment of choice in the early stages of GC is surgery. Due to high potential of malignancy, postoperative chemotherapy is usually administered. Novel methods of treatment involve immunotherapeutic agents (IA). The new therapies seem to be a hopeful perspective for patients with advanced GC. In this review, we present the outcomes of clinical trials in GC treatment with IA and their mechanisms of action. Furthermore, we present the benefits and shortcomings of immunotherapy and describe potential directions for future research.

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  1. Morgan E, Arnold M, Camargo MC, et al. The current and future incidence and mortality of gastric cancer in 185 countries, 2020-40: A population-based modelling study. EClinicalMedicine. 2022; 47: 101404.
  2. Kenig J, Richter P. Treatment of gastric cancer in the older population. Nowotwory. Journal of Oncology. 2021; 71(4): 245–250.
  3. Hu HM, Tsai HJ, Ku HY, et al. Survival outcomes of management in metastatic gastric adenocarcinoma patients. Sci Rep. 2021; 11(1): 23142.
  4. Smyth E, Nilsson M, Grabsch H, et al. Gastric cancer. Lancet. 2020; 396(10251): 635–648.
  5. Bang YJ, Van Cutsem E, Feyereislova A, et al. ToGA Trial Investigators. 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. Lancet. 2010; 376(9742): 687–697.
  6. Szklener K, Piwoński M, Żak K, et al. Management of hepatocellular carcinoma with novel immunotherapeutic agents and prospects for the future. Nowotwory. Journal of Oncology. 2021; 71(6): 391–400.
  7. Biagioni A, Skalamera I, Peri S, et al. Update on gastric cancer treatments and gene therapies. Cancer Metastasis Rev. 2019; 38(3): 537–548.
  8. Arienti C, Pignatta S, Tesei A. Epidermal Growth Factor Receptor Family and its Role in Gastric Cancer. Front Oncol. 2019; 9: 1308.
  9. Iqbal N, Iqbal N. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol Biol Int. 2014; 2014: 852748.
  10. Boku N. HER2-positive gastric cancer. Gastric Cancer. 2014; 17(1): 1–12.
  11. Palle J, Rochand A, Pernot S, et al. Human Epidermal Growth Factor Receptor 2 (HER2) in Advanced Gastric Cancer: Current Knowledge and Future Perspectives. Drugs. 2020; 80(4): 401–415.
  12. Abrahao-Machado LF, Scapulatempo-Neto C. HER2 testing in gastric cancer: An update. World J Gastroenterol. 2016; 22(19): 4619–4625.
  13. Croxtall JD, McKeage K. Trastuzumab: in HER2-positive metastatic gastric cancer. Drugs. 2010; 70(17): 2259–2267.
  14. Merchant SJ, Kong W, Gyawali B, et al. Effectiveness of Trastuzumab in Routine Clinical Practice: A Population-based Study of Patients with HER-2-positive Oesophageal, Gastroesophageal and Gastric Cancer. Clin Oncol (R Coll Radiol). 2021; 33(3): 202–207.
  15. Cheng X, Lu Yi. A review of capecitabine-based adjuvant therapy for gastric cancer in the Chinese population. Future Oncol. 2018; 14(8): 771–779.
  16. Ryu MH, Yoo C, Kim JG, et al. Multicenter phase II study of trastuzumab in combination with capecitabine and oxaliplatin for advanced gastric cancer. Eur J Cancer. 2015; 51(4): 482–488.
  17. Rivera F, Romero C, Jimenez-Fonseca P, et al. Phase II study to evaluate the efficacy of Trastuzumab in combination with Capecitabine and Oxaliplatin in first-line treatment of HER2-positive advanced gastric cancer: HERXO trial. Cancer Chemother Pharmacol. 2019; 83(6): 1175–1181.
  18. Wang F, Liu TS, Yuan XL, et al. Trastuzumab plus docetaxel and capecitabine as a first-line treatment for HER2-positive advanced gastric or gastroesophageal junction cancer: a phase II, multicenter, open-label, single-arm study. Am J Cancer Res. 2020; 10(9): 3037–3046.
  19. Keam SJ. Trastuzumab Deruxtecan: First Approval. Drugs. 2020; 80(5): 501–508.
  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. Lancet Oncol. 2019; 20(6): 827–836.
  21. Shitara K, Bang YJ, Iwasa S, et al. DESTINY-Gastric01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med. 2020; 382(25): 2419–2430.
  22. Ballantyne A, Dhillon S. Trastuzumab emtansine: first global approval. Drugs. 2013; 73(7): 755–765.
  23. 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. Lancet Oncol. 2017; 18(5): 640–653.
  24. Le Joncour V, Martins A, Puhka M, et al. A Novel Anti-HER2 Antibody-Drug Conjugate XMT-1522 for HER2-Positive Breast and Gastric Cancers Resistant to Trastuzumab Emtansine. Mol Cancer Ther. 2019; 18(10): 1721–1730.
  25. Xu Z, Guo D, Jiang Z, et al. Novel HER2-Targeting Antibody-Drug Conjugates of Trastuzumab Beyond T-DM1 in Breast Cancer: Trastuzumab Deruxtecan(DS-8201a) and (Vic-)Trastuzumab Duocarmazine (SYD985). Eur J Med Chem. 2019; 183: 111682.
  26. Rinnerthaler G, Gampenrieder SP, Greil R. HER2 Directed Antibody-Drug-Conjugates beyond T-DM1 in Breast Cancer. Int J Mol Sci. 2019; 20(5).
  27. ZW25 Effective in HER2-Positive Cancers. Cancer Discov. 2019; 9(1): 8.
  28. Zhu Y, Tian T, Zou J, et al. Dual PI3K/mTOR inhibitor BEZ235 exerts extensive antitumor activity in HER2-positive gastric cancer. BMC Cancer. 2015; 15: 894.
  29. Richard S, Selle F, Lotz JP, et al. Pertuzumab and trastuzumab: the rationale way to synergy. An Acad Bras Cienc. 2016; 88 Suppl 1: 565–577.
  30. 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. Lancet Oncol. 2018; 19(10): 1372–1384.
  31. Wagner AD, Grabsch HI, Mauer M, et al. EORTC-1203-GITCG - the "INNOVATION"-trial: Effect of chemotherapy alone versus chemotherapy plus trastuzumab, versus chemotherapy plus trastuzumab plus pertuzumab, in the perioperative treatment of HER2 positive, gastric and gastroesophageal junction adenocarcinoma on pathologic response rate: a randomized phase II-intergroup trial of the EORTC-Gastrointestinal Tract Cancer Group, Korean Cancer Study Group and Dutch Upper GI-Cancer group. BMC Cancer. 2019; 19(1): 494.
  32. Kreutzfeldt J, Rozeboom B, Dey N, et al. The trastuzumab era: current and upcoming targeted HER2+ breast cancer therapies. Am J Cancer Res. 2020; 10(4): 1045–1067.
  33. Catenacci D, Kang YK, Park H, et al. Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22–05): a single-arm, phase 1b–2 trial. Lancet Oncol. 2020; 21(8): 1066–1076.
  34. Catenacci DVt, Rosales M, Chung HC, et al. MAHOGANY: margetuximab combination in HER2+ unresectable/metastatic gastric/gastroesophageal junction adenocarcinoma. Future Oncol. 2021; 17(10): 1155–1164.
  35. Wecker H, Waller CF. Afatinib. Recent Results Cancer Res. 2018; 211: 199–215.
  36. Ebert K, Zwingenberger G, Barbaria E, et al. Effects of trastuzumab and afatinib on kinase activity in gastric cancer cell lines. Mol Oncol. 2018; 12(4): 441–462.
  37. 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. Acta Oncol. 2021; 60(6): 785–793.
  38. Voigtlaender M, Schneider-Merck T, Trepel M. Lapatinib. Recent Results Cancer Res. 2018; 211: 19–44.
  39. Moehler M, Schad A, Maderer A, et al. EORTC Gastrointestinal Tract Cancer Group. Lapatinib with ECF/X in the first-line treatment of metastatic gastric cancer according to HER2neu and EGFR status: a randomized placebo-controlled phase II study (EORTC 40071). Cancer Chemother Pharmacol. 2018; 82(4): 733–739.
  40. Press MF, Ellis CE, Gagnon RC, et al. Lapatinib in Combination With Capecitabine Plus Oxaliplatin in Human Epidermal Growth Factor Receptor 2-Positive Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma: TRIO-013/LOGiC--A Randomized Phase III Trial. J Clin Oncol. 2016; 34(5): 443–451.
  41. Satoh T, Xu RH, Chung HC, et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN--a randomized, phase III study. J Clin Oncol. 2014; 32(19): 2039–2049.
  42. Hamzehlou S, Momeny M, Zandi Z, et al. Anti-tumor activity of neratinib, a pan-HER inhibitor, in gastric adenocarcinoma cells. Eur J Pharmacol. 2019; 863: 172705.
  43. Kim TM, Lee KW, Oh DY, et al. Phase 1 Studies of Poziotinib, an Irreversible Pan-HER Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors. Cancer Res Treat. 2018; 50(3): 835–842.
  44. 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. Gastric Cancer. 2019; 22(6): 1206–1214.
  45. Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res. 2020; 10(3): 727–742.
  46. Qin W, Hu L, Zhang X, et al. The Diverse Function of PD-1/PD-L Pathway Beyond Cancer. Front Immunol. 2019; 10: 2298.
  47. Wu X, Gu Z, Chen Y, et al. Application of PD-1 Blockade in Cancer Immunotherapy. Comput Struct Biotechnol J. 2019; 17: 661–674.
  48. Patel SP, Kurzrock R. PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy. Mol Cancer Ther. 2015; 14(4): 847–856.
  49. Gu L, Chen M, Guo D, et al. PD-L1 and gastric cancer prognosis: A systematic review and meta-analysis. PLoS One. 2017; 12(8): e0182692.
  50. Lin C, He H, Liu H, et al. Tumour-associated macrophages-derived CXCL8 determines immune evasion through autonomous PD-L1 expression in gastric cancer. Gut. 2019; 68(10): 1764–1773.
  51. Wang X, Wu WKK, Gao J, et al. Autophagy inhibition enhances PD-L1 expression in gastric cancer. J Exp Clin Cancer Res. 2019; 38(1): 140.
  52. Kamath SD, Kalyan A, Benson AlB. Pembrolizumab for the treatment of gastric cancer. Expert Rev Anticancer Ther. 2018; 18(12): 1177–1187.
  53. Fuchs CS, Doi T, Jang RW, et al. Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial. JAMA Oncol. 2018; 4(5): e180013.
  54. Shitara K, Özgüroğlu M, Bang YJ, et al. KEYNOTE-061 investigators. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 2018; 392(10142): 123–133.
  55. Fuchs CS, Özgüroğlu M, Bang YJ, et al. Pembrolizumab versus paclitaxel for previously treated PD-L1-positive advanced gastric or gastroesophageal junction cancer: 2-year update of the randomized phase 3 KEYNOTE-061 trial. Gastric Cancer. 2022; 25(1): 197–206.
  56. Shitara K, Cutsem EV, Bang YJ, et al. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer. JAMA Oncol. 2020; 6(10): 1571–1580.
  57. Kawazoe A, Yamaguchi K, Yasui H, et al. Safety and efficacy of pembrolizumab in combination with S-1 plus oxaliplatin as a first-line treatment in patients with advanced gastric/gastroesophageal junction cancer: Cohort 1 data from the KEYNOTE-659 phase IIb study. Eur J Cancer. 2020; 129: 97–106.
  58. Chung HC, Bang YJ, S Fuchs C, et al. First-line pembrolizumab/placebo plus trastuzumab and chemotherapy in HER2-positive advanced gastric cancer: KEYNOTE-811. Future Oncol. 2021; 17(5): 491–501.
  59. Tabernero J, Bang YJ, Van Cutsem E, et al. KEYNOTE-859: a Phase III study of pembrolizumab plus chemotherapy in gastric/gastroesophageal junction adenocarcinoma. Future Oncol. 2021; 17(22): 2847–2855.
  60. Kono K, Nakajima S, Mimura K. Current status of immune checkpoint inhibitors for gastric cancer. Gastric Cancer. 2020; 23(4): 565–578.
  61. Kang YK, Boku N, Satoh T, et al. 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. 2017; 390(10111): 2461–2471.
  62. Kato K, Cho BC, Takahashi M, et al. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019; 20(11): 1506–1517.
  63. Boku N, Ryu MH, Kato K, et al. Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4). Ann Oncol. 2019; 30(2): 250–258.
  64. Kang YK, Chen LT, Ryu MH, et al. 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. 2022; 23(2): 234–247.
  65. Roviello G, D'Angelo A, Generali D, et al. Avelumab in gastric cancer. Immunotherapy. 2019; 11(9): 759–768.
  66. Bang YJ, Ruiz EY, Van Cutsem E, et al. Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann Oncol. 2018; 29(10): 2052–2060.
  67. Moehler M, Dvorkin M, Boku N, et al. Phase III Trial of Avelumab Maintenance After First-Line Induction Chemotherapy Versus Continuation of Chemotherapy in Patients With Gastric Cancers: Results From JAVELIN Gastric 100. J Clin Oncol. 2021; 39(9): 966–977.
  68. Bang YJ, Golan T, Dahan L, et al. Ramucirumab and durvalumab for previously treated, advanced non-small-cell lung cancer, gastric/gastro-oesophageal junction adenocarcinoma, or hepatocellular carcinoma: An open-label, phase Ia/b study (JVDJ). Eur J Cancer. 2020; 137: 272–284.
  69. Kelly RJ, Lee J, Bang YJ, et al. Safety and Efficacy of Durvalumab and Tremelimumab Alone or in Combination in Patients with Advanced Gastric and Gastroesophageal Junction Adenocarcinoma. Clin Cancer Res. 2020; 26(4): 846–854.
  70. Evrard C, Louvet C, Hajbi FEl, et al. PRODIGE 59-DURIGAST trial: A randomised phase II study evaluating FOLFIRI + Durvalumab ± Tremelimumab in second-line of patients with advanced gastric cancer. Dig Liver Dis. 2021; 53(4): 420–426.
  71. Janjigian YY, Van Cutsem E, Muro K, et al. MATTERHORN: phase III study of durvalumab plus FLOT chemotherapy in resectable gastric/gastroesophageal junction cancer. Future Oncol. 2022; 18(20): 2465–2473.
  72. Yu S, Yi M, Qin S, et al. Next generation chimeric antigen receptor T cells: safety strategies to overcome toxicity. Mol Cancer. 2019; 18(1): 125.
  73. Chmielewski M, Abken H. TRUCKs: the fourth generation of CARs. Expert Opin Biol Ther. 2015; 15(8): 1145–1154.
  74. June CH, Sadelain M. Chimeric Antigen Receptor Therapy. N Engl J Med. 2018; 379(1): 64–73.
  75. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016; 127(26): 3321–3330.
  76. Jiang H, Shi Z, Wang P, et al. Claudin18.2-Specific Chimeric Antigen Receptor Engineered T Cells for the Treatment of Gastric Cancer. J Natl Cancer Inst. 2019; 111(4): 409–418.
  77. Sampera A, Sánchez-Martín FJ, Arpí O, et al. HER-Family Ligands Promote Acquired Resistance to Trastuzumab in Gastric Cancer. Mol Cancer Ther. 2019; 18(11): 2135–2145.
  78. Tang L, Long Z, Zhao Na, et al. NES1/KLK10 promotes trastuzumab resistance via activation of PI3K/AKT signaling pathway in gastric cancer. J Cell Biochem. 2018; 119(8): 6398–6407.
  79. Wang W, Wang S, Xu AM, et al. Overexpression of GSE1 Related to Trastuzumab Resistance in Gastric Cancer Cells. Biomed Res Int. 2021; 2021: 8834923.
  80. Wang S, Zhao Y, Song Y, et al. ERBB2D16 Expression in HER2 Positive Gastric Cancer Is Associated With Resistance to Trastuzumab. Front Oncol. 2022; 12: 855308.
  81. Wang DS, Liu ZX, Lu YX, et al. Liquid biopsies to track trastuzumab resistance in metastatic HER2-positive gastric cancer. Gut. 2019; 68(7): 1152–1161.
  82. Ebert K, Haffner I, Zwingenberger G, et al. Combining gene expression analysis of gastric cancer cell lines and tumor specimens to identify biomarkers for anti-HER therapies-the role of HAS2, SHB and HBEGF. BMC Cancer. 2022; 22(1): 254.
  83. Sawaya S, Bagshaw A, Buschiazzo E, et al. Microsatellite tandem repeats are abundant in human promoters and are associated with regulatory elements. PLoS One. 2013; 8(2): e54710.
  84. Baretti M, Le DT. DNA mismatch repair in cancer. Pharmacol Ther. 2018; 189: 45–62.
  85. Puliga E, Corso S, Pietrantonio F, et al. Microsatellite instability in Gastric Cancer: Between lights and shadows. Cancer Treat Rev. 2021; 95: 102175.
  86. Marabelle A, Le DT, Ascierto PA, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2020; 38(1): 1–10.
  87. Wang YL, Gong Y, Lv Z, et al. Expression of PD1/PDL1 in gastric cancer at different microsatellite status and its correlation with infiltrating immune cells in the tumor microenvironment. J Cancer. 2021; 12(6): 1698–1707.
  88. Saito M, Kono K. Landscape of EBV-positive gastric cancer. Gastric Cancer. 2021; 24(5): 983–989.
  89. Lima Á, Sousa H, Medeiros R, et al. PD-L1 expression in EBV associated gastric cancer: a systematic review and meta-analysis. Discov Oncol. 2022; 13(1): 19.
  90. Alessandrini L, Manchi M, De Re V, et al. Proposed Molecular and miRNA Classification of Gastric Cancer. Int J Mol Sci. 2018; 19(6).
  91. Chen Di, Ping S, Xu Y, et al. Non-Coding RNAs in Gastric Cancer: From Malignant Hallmarks to Clinical Applications. Front Cell Dev Biol. 2021; 9: 732036.
  92. Li W, Liu JQ, Chen M, et al. Circular RNA in cancer development and immune regulation. J Cell Mol Med. 2022; 26(6): 1785–1798.
  93. Chen DL, Sheng H, Zhang DS, et al. The circular RNA circDLG1 promotes gastric cancer progression and anti-PD-1 resistance through the regulation of CXCL12 by sponging miR-141-3p. Mol Cancer. 2021; 20(1): 166.
  94. Li C, Shen Q, Zhang P, et al. Targeting MUS81 promotes the anticancer effect of WEE1 inhibitor and immune checkpoint blocking combination therapy via activating cGAS/STING signaling in gastric cancer cells. J Exp Clin Cancer Res. 2021; 40(1): 315.
  95. Sahin U, Türeci Ö, Manikhas G, et al. FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol. 2021; 32(5): 609–619.

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