Prognostic Impact of Immune-Related Adverse Events in Advanced Gastric Cancer Patients Treated with Immune Checkpoint Inhibitors: A Real-world Retrospective Study
-
Lianxing Zhang
,
Xia Han
,
Yue Wang
,
Yanrong Li
,
Jia Wang
Abstract
While immune checkpoint inhibitors (ICIs) are a key treatment for advanced gastric cancer (AGC), the prognostic significance of their associated immune-related adverse events (irAEs) remains unclear. This real-world study aims to evaluate irAE incidence and impact on clinical outcomes.
This retrospective study consecutively enrolled 156 patients with AGC who received ICI therapy and completed follow-up between January 2021 and June 2023. Baseline characteristics, treatment regimens, irAE occurrence, and survival data were collected. The prognostic impact of irAEs was assessed by objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).
A total of 156 patients were included, of whom 76 (48.72%) developed irAEs. The most common types were endocrine, cutaneous, and gastrointestinal toxicities, mostly of grades 1-2. Multivariate logistic regression analysis identified age≥70 years (OR=2.615), BMI ≥ 25 kg/m² (OR=5.791), prior chemotherapy (OR=4.954), prior targeted therapy (OR=5.532), ICI combined with chemotherapy (OR=5.456), ICI combined with targeted therapy (OR=2.850), and a history of smoking (OR=3.224) as independent predictors of irAEs. Compared with the non-irAEs group, the irAEs group showed superior clinical efficacy, with a significantly higher ORR (38.16% vs. 20.00%) and DCR (80.26% vs. 66.25%). Kaplan-Meier survival analysis revealed a significant association between the occurrence of irAEs and prolonged survival, with the irAEs group showing superior median PFS (8.0 vs. 5.0 months) and OS (15.0 vs. 10.0 months) compared to the non-irAEs group.
For AGC patients receiving ICI therapy, the development of irAEs correlates significantly with improved survival, serving as a potential biomarker of clinical benefit.
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3. Kim R, An M, Lee H, Mehta A, Heo YJ, Kim KM, et al. Early tumor-immune microenvironmental remodeling and response to first-line fluoropyrimidine and platinum chemotherapy in advanced gastric cancer. Cancer Discov.2022;12(4):984-1001.
4. Senthil M, Dayyani F. Phase II clinical trial of sequential treatment with systemic chemotherapy and intraperitoneal paclitaxel for gastric and gastroesophageal junction peritoneal carcinomatosis - STOPGAP trial. BMC Cancer.2023;23(1):209.
5. Fuchs CS, ?zg?ro?lu M, Bang YJ, Di Bartolomeo M, Mandala M, Ryu MH, 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.
6. Koo DH, Ryu MH, Lee MY, Chae H, Kim EJ, Moon MS, et al. Trends in chemotherapy patterns and survival of patients with advanced gastric cancer over a 16-year period: impact of anti-HER2-targeted agent in the real-world setting. Cancer Res Treat. 2021;53(2):436-44.
7. Ye M, Xiu LJ, Ji QQ, Zhang YC, Sun YW, Zhao Y, et al. Research progress in targeted therapies for gastric cancer. Int J Clin Pharmacol Ther. 2022;60(12):509-14.
8. Li S, Yu W, Xie F, Luo H, Liu Z, Lv W, et al. Neoadjuvant therapy with immune checkpoint blockade, antiangiogenesis, and chemotherapy for locally advanced gastric cancer. Nat Commun. 2023;14(1):8.
9. Wang M, Li J, Shen S, Chen L, Jia B. Comparative efficacy and safety of distinct PD-1 antibodies in unresectable advanced or recurrent gastric and gastroesophageal junction cancer: a network meta-analysis of randomized controlled trials. BMC Gastroenterol. 2025;25(1):847.
10. Blum SM, Rouhani SJ, Sullivan RJ. Effects of immune-related adverse events (irAEs) and their treatment on antitumor immune responses. Immunol Rev. 2023;318(1):167-78.
11. Zhang Y, Chen J, Liu H, Dai J, Zhao J, Zhu S, et al. The incidence of immune-related adverse events (irAEs) and their association with clinical outcomes in advanced renal cell carcinoma and urothelial carcinoma patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Cancer Treat Rev. 2024;129:102787.
12. Poto R, Troiani T, Criscuolo G, Marone G, Ciardiello F, Tocchetti CG, et al. Holistic approach to immune checkpoint inhibitor-related adverse events. Front Immunol. 2022;13:804597.
13. Wu CE, Yang CK, Peng MT, Huang PW, Chang CF, Yeh KY, et al. The association between immune-related adverse events and survival outcomes in Asian patients with advanced melanoma receiving anti-PD-1 antibodies. BMC Cancer. 2020;20(1):1018.
14. Xie X, Li Y, Lv Q, Wang W, Ding W, Li Y. Immune-related adverse events correlate with the clinical efficacy in advanced non-small-cell lung cancer patients treated with PD-1 inhibitors combination therapy. BMC Cancer.2024;24(1):1541.
15. Yasuda Y, Fujiwara R, Oguchi T, Komai Y, Numao N, Yamamoto S, et al. Prognostic significance of immune-related adverse events in metastatic renal cell carcinoma patients treated with immune-checkpoint-inhibitors. Cancer Diagn Progn. 2023;3(3):327-33.
16. Otsuka H, Kita Y, Ito K, Sano T, Inokuchi J, Tomida R, et al. Immune-related adverse events in urothelial cancer patients: adjustment for immortal time bias. Cancer Sci. 2022;113(11):3912-21.
17. Kono Y, Choda Y, Nakagawa M, Miyahara K, Ishida M, Kubota T, et al. Association between immune-related adverse events and the prognosis of patients with advanced gastric cancer treated with nivolumab. Target Oncol.2021;16(2):237-48.
18. Ishido K, Tanabe S, Katada C, Ishibashi Y, Kitahara G, Onoue M, et al. Evaluation of prognostic factors for unresectable or recurrent gastric cancer treated with nivolumab. J Gastrointest Cancer. 2023;54(2):485-91.
19. Matsunaga T, Saito H, Kuroda H, Osaki T, Takahashi S, Iwamoto A, et al. CA19-9 in combination with P-CRP as a predictive marker of immune-related adverse events in patients with recurrent or unresectable advanced gastric cancer treated with nivolumab. BMC Cancer. 2022;22(1):418.
20. Suematsu H, Kano K, Yamada T, Hashimoto I, Watanabe H, Takahashi K, et al. Prognostic impact of immune-related adverse events in gastric cancer patients treated with nivolumab. Anticancer Res. 2022;42(3):1535-40.
21. Namikawa T, Yokota K, Tanioka N, Fukudome I, Iwabu J, Munekage M, et al. Systemic inflammatory response and nutritional biomarkers as predictors of nivolumab efficacy for gastric cancer. Surg Today. 2020;50(11):1486-95.
22. Toyozumi T, Shimada H, Matsubara H. Immune checkpoint inhibitors in gastrointestinal cancers: current evidence and future directions. Oncol Res. 2025;33(11):3185-206.
23. Teng YS, Yu S. Molecular mechanisms of cutaneous immune-related adverse events (irAEs) induced by immune checkpoint inhibitors. Curr Oncol. 2023;30(7):6805-19.
24. Ramos-Casals M, Sis?-Almirall A. Immune-related adverse events of immune checkpoint inhibitors. Ann Intern Med. 2024;177(2):ITC17-ITC32.
25. Chhabra N, Kennedy J. A review of cancer immunotherapy toxicity: immune checkpoint inhibitors. J Med Toxicol.2021;17(4):411-24.
26. Ashrafizadeh M. Cell death mechanisms in human cancers: molecular pathways, therapy resistance and therapeutic perspective. J Cancer Biomol Ther. 2024;1(1):17-40.
27. Ren J. Advances in combination therapy for gastric cancer: integrating targeted agents and immunotherapy. Adv Clin Pharmacol Ther. 2024;1(1):1-15.
28. Fu X, Li F, You H, Xu B, Wang T, Qin P, et al. The baseline circulating immunophenotype characteristics associate with PD(L)-1 targeted treatment response, irae onset, and prognosis. Sci Rep. 2025;15(1):17450.
29. Wang SJ, Dougan SK, Dougan M. Immune mechanisms of toxicity from checkpoint inhibitors. Trends Cancer.2023;9(7):543-53.
30. Weinmann SC, Pisetsky DS. Mechanisms of immune-related adverse events during the treatment of cancer with immune checkpoint inhibitors. Rheumatology (Oxford). 2019;58(Suppl 7):vii59-vii67.
31. Sutanto H, Safira A, Fetarayani D. From tumor to tolerance: a comprehensive review of immune checkpoint inhibitors and immune-related adverse events. Asia Pac Allergy. 2024;14(3):124-38.
32. Wong CK, Lam TH, Liao SY, Lau YM, Tse HF, So BYF. Immunopathogenesis of immune checkpoint inhibitor induced myocarditis: insights from experimental models and treatment implications. Biomedicines. 2023;11(1).
33. Pei WG, Chen WZ, Wu YK, Tan SX, Jie ZG. Immune-related adverse events associated with immune checkpoint inhibitors for advanced gastric and gastroesophageal junction cancer: a meta-analysis. World J Gastrointest Oncol. 2023;15(2):352-67.
34. Jayathilaka B, Mian F, Franchini F, Au-Yeung G, Ijzerman M, et al. Cancer and treatment specific incidence rates of immune-related adverse events induced by immune checkpoint inhibitors: a systematic review. Br J Cancer.2025;132(1):51-7.
35. Baldini C, Martin Romano P, Voisin AL, Danlos FX, Champiat S, Laghouati S, et al. Impact of aging on immune-related adverse events generated by anti-programmed death (ligand) PD-(L)1 therapies. Eur J Cancer.2020;129:71-9.
36. Wu F, Mu WC, Markov NT, Fuentealba M, Halaweh H, Senchyna F, et al. Immunological biomarkers of aging. J Immunol. 2025;214(5):889-902.
37. Guzman-Prado Y, Ben Shimol J, Samson O. Body mass index and immune-related adverse events in patients on immune checkpoint inhibitor therapies: a systematic review and meta-analysis. Cancer Immunol Immunother.2021;70(1):89-100.
38. Cortellini A, Bersanelli M, Santini D, Buti S, Tiseo M, Cannita K, et al. Another side of the association between body mass index (BMI) and clinical outcomes of cancer patients receiving PD-1/PD-L1 checkpoint inhibitors: a multicentre analysis of immune-related adverse events. Eur J Cancer. 2020;128:17-26.
39. Zheng J, Huang B, Xiao L, Wu M, Li J. Treatment- and immune-related adverse events of immune checkpoint inhibitors in esophageal or gastroesophageal junction cancer: a network meta-analysis of randomized controlled trials. Front Oncol. 2022;12:821626.
40. Muthumalage T, Rahman I. Pulmonary immune response regulation, genotoxicity, and metabolic reprogramming by menthol- and tobacco-flavored e-cigarette exposures in mice. Toxicol Sci. 2023;193(2):146-65.
2. Al-Haddad MA, Elhanafi SE, Forbes N, Thosani NC, Draganov PV, Othman MO, et al. American Society for Gastrointestinal Endoscopy guideline on endoscopic submucosal dissection for the management of early esophageal and gastric cancers: methodology and review of evidence. Gastrointest Endosc. 2023;98(3):285-305.e38.
3. Kim R, An M, Lee H, Mehta A, Heo YJ, Kim KM, et al. Early tumor-immune microenvironmental remodeling and response to first-line fluoropyrimidine and platinum chemotherapy in advanced gastric cancer. Cancer Discov.2022;12(4):984-1001.
4. Senthil M, Dayyani F. Phase II clinical trial of sequential treatment with systemic chemotherapy and intraperitoneal paclitaxel for gastric and gastroesophageal junction peritoneal carcinomatosis - STOPGAP trial. BMC Cancer.2023;23(1):209.
5. Fuchs CS, ?zg?ro?lu M, Bang YJ, Di Bartolomeo M, Mandala M, Ryu MH, 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.
6. Koo DH, Ryu MH, Lee MY, Chae H, Kim EJ, Moon MS, et al. Trends in chemotherapy patterns and survival of patients with advanced gastric cancer over a 16-year period: impact of anti-HER2-targeted agent in the real-world setting. Cancer Res Treat. 2021;53(2):436-44.
7. Ye M, Xiu LJ, Ji QQ, Zhang YC, Sun YW, Zhao Y, et al. Research progress in targeted therapies for gastric cancer. Int J Clin Pharmacol Ther. 2022;60(12):509-14.
8. Li S, Yu W, Xie F, Luo H, Liu Z, Lv W, et al. Neoadjuvant therapy with immune checkpoint blockade, antiangiogenesis, and chemotherapy for locally advanced gastric cancer. Nat Commun. 2023;14(1):8.
9. Wang M, Li J, Shen S, Chen L, Jia B. Comparative efficacy and safety of distinct PD-1 antibodies in unresectable advanced or recurrent gastric and gastroesophageal junction cancer: a network meta-analysis of randomized controlled trials. BMC Gastroenterol. 2025;25(1):847.
10. Blum SM, Rouhani SJ, Sullivan RJ. Effects of immune-related adverse events (irAEs) and their treatment on antitumor immune responses. Immunol Rev. 2023;318(1):167-78.
11. Zhang Y, Chen J, Liu H, Dai J, Zhao J, Zhu S, et al. The incidence of immune-related adverse events (irAEs) and their association with clinical outcomes in advanced renal cell carcinoma and urothelial carcinoma patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Cancer Treat Rev. 2024;129:102787.
12. Poto R, Troiani T, Criscuolo G, Marone G, Ciardiello F, Tocchetti CG, et al. Holistic approach to immune checkpoint inhibitor-related adverse events. Front Immunol. 2022;13:804597.
13. Wu CE, Yang CK, Peng MT, Huang PW, Chang CF, Yeh KY, et al. The association between immune-related adverse events and survival outcomes in Asian patients with advanced melanoma receiving anti-PD-1 antibodies. BMC Cancer. 2020;20(1):1018.
14. Xie X, Li Y, Lv Q, Wang W, Ding W, Li Y. Immune-related adverse events correlate with the clinical efficacy in advanced non-small-cell lung cancer patients treated with PD-1 inhibitors combination therapy. BMC Cancer.2024;24(1):1541.
15. Yasuda Y, Fujiwara R, Oguchi T, Komai Y, Numao N, Yamamoto S, et al. Prognostic significance of immune-related adverse events in metastatic renal cell carcinoma patients treated with immune-checkpoint-inhibitors. Cancer Diagn Progn. 2023;3(3):327-33.
16. Otsuka H, Kita Y, Ito K, Sano T, Inokuchi J, Tomida R, et al. Immune-related adverse events in urothelial cancer patients: adjustment for immortal time bias. Cancer Sci. 2022;113(11):3912-21.
17. Kono Y, Choda Y, Nakagawa M, Miyahara K, Ishida M, Kubota T, et al. Association between immune-related adverse events and the prognosis of patients with advanced gastric cancer treated with nivolumab. Target Oncol.2021;16(2):237-48.
18. Ishido K, Tanabe S, Katada C, Ishibashi Y, Kitahara G, Onoue M, et al. Evaluation of prognostic factors for unresectable or recurrent gastric cancer treated with nivolumab. J Gastrointest Cancer. 2023;54(2):485-91.
19. Matsunaga T, Saito H, Kuroda H, Osaki T, Takahashi S, Iwamoto A, et al. CA19-9 in combination with P-CRP as a predictive marker of immune-related adverse events in patients with recurrent or unresectable advanced gastric cancer treated with nivolumab. BMC Cancer. 2022;22(1):418.
20. Suematsu H, Kano K, Yamada T, Hashimoto I, Watanabe H, Takahashi K, et al. Prognostic impact of immune-related adverse events in gastric cancer patients treated with nivolumab. Anticancer Res. 2022;42(3):1535-40.
21. Namikawa T, Yokota K, Tanioka N, Fukudome I, Iwabu J, Munekage M, et al. Systemic inflammatory response and nutritional biomarkers as predictors of nivolumab efficacy for gastric cancer. Surg Today. 2020;50(11):1486-95.
22. Toyozumi T, Shimada H, Matsubara H. Immune checkpoint inhibitors in gastrointestinal cancers: current evidence and future directions. Oncol Res. 2025;33(11):3185-206.
23. Teng YS, Yu S. Molecular mechanisms of cutaneous immune-related adverse events (irAEs) induced by immune checkpoint inhibitors. Curr Oncol. 2023;30(7):6805-19.
24. Ramos-Casals M, Sis?-Almirall A. Immune-related adverse events of immune checkpoint inhibitors. Ann Intern Med. 2024;177(2):ITC17-ITC32.
25. Chhabra N, Kennedy J. A review of cancer immunotherapy toxicity: immune checkpoint inhibitors. J Med Toxicol.2021;17(4):411-24.
26. Ashrafizadeh M. Cell death mechanisms in human cancers: molecular pathways, therapy resistance and therapeutic perspective. J Cancer Biomol Ther. 2024;1(1):17-40.
27. Ren J. Advances in combination therapy for gastric cancer: integrating targeted agents and immunotherapy. Adv Clin Pharmacol Ther. 2024;1(1):1-15.
28. Fu X, Li F, You H, Xu B, Wang T, Qin P, et al. The baseline circulating immunophenotype characteristics associate with PD(L)-1 targeted treatment response, irae onset, and prognosis. Sci Rep. 2025;15(1):17450.
29. Wang SJ, Dougan SK, Dougan M. Immune mechanisms of toxicity from checkpoint inhibitors. Trends Cancer.2023;9(7):543-53.
30. Weinmann SC, Pisetsky DS. Mechanisms of immune-related adverse events during the treatment of cancer with immune checkpoint inhibitors. Rheumatology (Oxford). 2019;58(Suppl 7):vii59-vii67.
31. Sutanto H, Safira A, Fetarayani D. From tumor to tolerance: a comprehensive review of immune checkpoint inhibitors and immune-related adverse events. Asia Pac Allergy. 2024;14(3):124-38.
32. Wong CK, Lam TH, Liao SY, Lau YM, Tse HF, So BYF. Immunopathogenesis of immune checkpoint inhibitor induced myocarditis: insights from experimental models and treatment implications. Biomedicines. 2023;11(1).
33. Pei WG, Chen WZ, Wu YK, Tan SX, Jie ZG. Immune-related adverse events associated with immune checkpoint inhibitors for advanced gastric and gastroesophageal junction cancer: a meta-analysis. World J Gastrointest Oncol. 2023;15(2):352-67.
34. Jayathilaka B, Mian F, Franchini F, Au-Yeung G, Ijzerman M, et al. Cancer and treatment specific incidence rates of immune-related adverse events induced by immune checkpoint inhibitors: a systematic review. Br J Cancer.2025;132(1):51-7.
35. Baldini C, Martin Romano P, Voisin AL, Danlos FX, Champiat S, Laghouati S, et al. Impact of aging on immune-related adverse events generated by anti-programmed death (ligand) PD-(L)1 therapies. Eur J Cancer.2020;129:71-9.
36. Wu F, Mu WC, Markov NT, Fuentealba M, Halaweh H, Senchyna F, et al. Immunological biomarkers of aging. J Immunol. 2025;214(5):889-902.
37. Guzman-Prado Y, Ben Shimol J, Samson O. Body mass index and immune-related adverse events in patients on immune checkpoint inhibitor therapies: a systematic review and meta-analysis. Cancer Immunol Immunother.2021;70(1):89-100.
38. Cortellini A, Bersanelli M, Santini D, Buti S, Tiseo M, Cannita K, et al. Another side of the association between body mass index (BMI) and clinical outcomes of cancer patients receiving PD-1/PD-L1 checkpoint inhibitors: a multicentre analysis of immune-related adverse events. Eur J Cancer. 2020;128:17-26.
39. Zheng J, Huang B, Xiao L, Wu M, Li J. Treatment- and immune-related adverse events of immune checkpoint inhibitors in esophageal or gastroesophageal junction cancer: a network meta-analysis of randomized controlled trials. Front Oncol. 2022;12:821626.
40. Muthumalage T, Rahman I. Pulmonary immune response regulation, genotoxicity, and metabolic reprogramming by menthol- and tobacco-flavored e-cigarette exposures in mice. Toxicol Sci. 2023;193(2):146-65.
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| Checkpoint inhibitors Drug-related side effects and adverse reactions Immune system Prognosis Stomach neoplasms | ||
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How to Cite
1.
Zhang L, Han X, Wang Y, Li Y, Wang J. Prognostic Impact of Immune-Related Adverse Events in Advanced Gastric Cancer Patients Treated with Immune Checkpoint Inhibitors: A Real-world Retrospective Study. Iran J Allergy Asthma Immunol. 2026;:1-15.
