Biomarker-based long-term safety and efficacy of PD-1/PD-L1 inhibitors combined with chemotherapy in advanced gastroesophageal carcinomas: A systematic review and meta-analysis

Abstract

Advanced gastroesophageal cancers often have poor survival rates even with chemotherapy. We aim to study the long-term safety and efficacy of combining PD-1/PD-L1 inhibitors with chemotherapy, incorporating biomarker analysis and recent Phase III trial data. Data from eight phase III trials (from inception to 2025, comprising 5668 patients) was combined in this PRISMA-guided meta-analysis. Overall survival (OS), objective response rate (ORR), progression-free survival (PFS), and grade ≥3 adverse events were among the outcomes. Random-effects models were employed for statistical synthesis, and I² was used to assess the heterogeneity. Cochrane RoB 2.0 was used to evaluate the risk of bias. Compared to chemotherapy alone, the combined regimen significantly improved overall survival (HR: 0.79; 95% CI: 0.75–0.83; p < .0001), progression-free survival (HR: 0.73; 95% CI: 0.68–0.78; p < .00001), and objective response rate (OR: 1.60; 95% CI: 1.44–1.78; p < .0001). The CPS ≥10 subgroups showed the greatest benefits (OS HR, 0.66; PFS HR, 0.63; p < .0001). Although manageable, grade ≥3 adverse events (OR, 1.37; 95% CI: 1.20–1.56) and immune-related toxicities (OR: 3.44; 95% CI: 2.91–4.08) were more common with ICIs. The OS advantage was greatest for MSI-high tumors (HR: 0.54; p < .04), but was not significant for esophageal cancers (HR: 0.88; p < .18). With long-lasting improvements in survival and manageable toxicity, PD-1/PD-L1 inhibitors in combination with chemotherapy constitute the first-line standard for advanced gastric/GEJ malignancies. Immune checkpoint inhibitors show a higher incidence of adverse events, and clinicians should balance efficacy against adverse event risk.

Keywords

combination therapy / gastric cancer / gastroesophageal junction carcinoma / PD-1 inhibitor / PD-L1 inhibitor

References

[1] Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71(3): 209-249.

[2] 905-northern-america-fact-sheet.pdf [Internet]. Accessed March 9, 2025. https://gco.iarc.who.int/media/globocan/factsheets/populations/905-northern-america-fact-sheet.pdf

[3] 908-europe-fact-sheet.pdf [Internet]. Accessed March 9, 2025. https://gco.iarc.who.int/media/globocan/factsheets/populations/908-europe-fact-sheet.pdf

[4] 935-asia-fact-sheet.pdf [Internet]. Accessed March 9, 2025. https://gco.iarc.who.int/media/globocan/factsheets/populations/935-asia-fact-sheet.pdf

[5] Cao W, Chen HD, Yu YW, Li N, Chen WQ. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the Global Cancer Statistics 2020. Chin Med J (Engl). 2021; 134(7): 783-791.

[6] 392-japan-fact-sheet.pdf [Internet]. Accessed March 9, 2025. https://gco.iarc.who.int/media/globocan/factsheets/populations/392-japan-fact-sheet.pdf

[7] 410-korea-republic-of-fact-sheet.pdf [Internet]. Accessed March 9, 2025. https://gco.iarc.who.int/media/globocan/factsheets/populations/410-korea-republic-of-fact-sheet.pdf

[8] Lagergren J, Smyth E, Cunningham D, Lagergren P. Oesophageal cancer. Lancet. 2017; 390(10110): 2383-2396.

[9] Kamangar F. The global, regional, and national burden of oesophageal cancer and its attributable risk factors in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020; 5(6): 582-597.

[10] Stomach Cancer Survival Rates and Statistics—NCI [Internet]. 2023 Accessed March 9, 2025. https://www.cancer.gov/types/stomach/survival

[11] Statistics for Esophageal Cancer. Esophageal Cancer Stats [Internet]. Accessed March 9, 2025. https://www.cancer.org/cancer/types/esophagus-cancer/about/key-statistics.html

[12] Fuchs CS, Shitara K, Di Bartolomeo M, et al. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2019; 20(3): 420-435.

[13] Kang YK, Kang WK, Shin DB, et al. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009; 20(4): 666-673.

[14] Janjigian YY, Bendell J, Calvo E, et al. CheckMate-032 study: efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer. J Clin Oncol. 2018; 36(28): 2836-2844.

[15] Shah MA, Bang YJ, Lordick F, et al. Effect of fluorouracil, leucovorin, and oxaliplatin with or without onartuzumab in HER2-negative, MET-positive gastroesophageal adenocarcinoma: the METGastric randomized clinical trial. JAMA Oncol. 2017; 3(5): 620-627.

[16] Wang FH, Zhang XT, Tang L, et al. The Chinese Society of Clinical Oncology (CSCO): clinical guidelines for the diagnosis and treatment of gastric cancer, 2023. Cancer Commun. 2024; 44(1): 127-172.

[17] Marin-Acevedo JA, Kimbrough EO, Lou Y. Next generation of immune checkpoint inhibitors and beyond. J Hematol Oncol. 2021; 14(1): 45.

[18] Sun Q, Hong Z, Zhang C, Wang L, Han Z, Ma D. Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends. Signal Transduct Target Ther. 2023; 8(1):320.

[19] Beshr MS, Beshr IA, Al Hayek M, et al. PD-1/PD-L1 inhibitors in combination with chemo or as monotherapy vs. chemotherapy alone in advanced, unresectable HER2-negative gastric, gastroesophageal junction, and esophageal adenocarcinoma: a meta-analysis. Clin Oncol. 2024; 36(12): 797-808.

[20] 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.

[21] Zhang X, Wang J, Wang G, et al. First-line Sugemalimab plus chemotherapy for advanced gastric cancer: the GEMSTONE-303 randomized clinical trial. Jama. 2025;e2428463.

[22] Matthew JP. The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews—PubMed [Internet]. Accessed March 9, 2025. https://pubmed.ncbi.nlm.nih.gov/33782057/

[23] Delgado A, Guddati AK. Clinical endpoints in oncology—a primer. Am J Cancer Res. 2021; 11(4): 1121-1131.

[24] Liu C, Fang F, Kong Y, ElGabry EA. Tumor area positivity (TAP) score of programmed death-ligand 1 (PD-L1): a novel visual estimation method for combined tumor cell and immune cell scoring. Diagn Pathol. 2023; 18(1):48.

[25] Puliga E. Microsatellite Instability in Gastric Cancer: Between Lights and Shadows—PubMed [Internet]. Accessed March 9, 2025. https://pubmed.ncbi.nlm.nih.gov/33721595/

[26] Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019; 366:l4898.

[27] 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 Lond Engl. 2021; 398(10294): 27-40.

[28] Domagala-Kulawik J. The role of the immune system in non-small cell lung carcinoma and potential for therapeutic intervention. Transl Lung Cancer Res. 2015; 4(2):3980. https://tlcr.amegroups.org/article/view/3980

[29] Wong DYQ, Ong WWF, Ang WH. Induction of immunogenic cell death by chemotherapeutic platinum complexes. Angew Chem Int Ed. 2015; 54(22): 6483-6487.

[30] Demaria S, Guha C, Schoenfeld J, et al. Radiation dose and fraction in immunotherapy: one-size regimen does not fit all settings, so how does one choose? J Immunother Cancer. 2021; 9(4):e002038.

[31] Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med. 2016; 375(18): 1767-1778.

[32] Huang J, Xu B, Mo H, et al. Safety, activity, and biomarkers of SHR-1210, an anti-PD-1 antibody, for patients with advanced esophageal carcinoma. Clin Cancer Res. 2018; 24(6): 1296-1304.

[33] Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol. 2018; 18(3): 153-167.

[34] Cortes J, Rugo HS, Cescon DW, et al. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022; 387(3): 217-226.

[35] Shitara K, Özgüroğlu M, Bang YJ, et al. 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.

[36] Lu Z, Wang J, Shu Y, et al. Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): multicentre, randomised, double blind, phase 3 trial. BMJ. 2022; 377:e068714.

[37] 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.

[38] Rha SY, Oh DY, Yañez 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.

[39] Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008; 358(1): 36-46.

[40] Zhou Q, Chen M, Jiang O, et al. Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage III non-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2022; 23(2): 209-219.

[41] Cheng C, Zhuge L, Xiao X, Luan S, Yuan Y. Overcoming resistance to PD-1/PD-L1 inhibitors in esophageal cancer. Front Oncol. 2022; 12:955163.

[42] Liu W, Huo G, Chen P. Efficacy of PD-1/PD-L1 inhibitors in advanced gastroesophageal cancer based on characteristics: a meta-analysis. Immunotherapy. 2023; 15(10): 751-771.

[43] Cochrane Handbook for Systematic Reviews of Interventions. [Internet]. Accessed March 15, 2025. https://training.cochrane.org/handbook/current

RIGHTS & PERMISSIONS

2026 The Author(s). Precision Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital.