Advanced gastric cancer remains one of the deadliest malignancies, with a 5-year overall survival rate below 10%. In recent years, combining chemotherapy with PD-1 or PD-L1 inhibitors has become standard first-line care for previously untreated HER2-negative disease. Yet major global trials and subgroup analyses have pointed to a recurring pattern: Asian patients often experience stronger antitumor responses and better survival outcomes than non-Asian patients. The reasons remain unclear, but may involve differences in age at diagnosis, tumor site, histologic type, disease stage, tumor burden, molecular subtype distribution, and immune biology. Based on these challenges, deeper research is needed to explain why treatment outcomes diverge across populations.
Published (DOI: 10.20892/j.issn.2095-3941.2025.0398) in Cancer Biology & Medicine, the review by researchers from The Fifth Medical Center of the Chinese PLA General Hospital and MSD China examines racial and regional differences in first-line immunotherapy outcomes for advanced HER2-negative gastric cancer, and explores how tumor biology, host immunity, infection, and environmental exposures may together shape those differences.
The authors reviewed evidence from key clinical studies, including KEYNOTE-062, CheckMate-649, KEYNOTE-859, ORIENT-16, KEYNOTE-590, RATIONALE-305, and other pivotal trials that helped establish immunotherapy plus chemotherapy as standard first-line treatment. Across these datasets, Asian patients frequently showed greater survival benefit than non-Asian patients. The review then traces possible reasons. Asian patients are often diagnosed younger, and in some countries such as Japan and South Korea, screening programs may support earlier detection and lower tumor burden. Tumor location and histology also differ, with non-Asian patients more often presenting proximal or diffuse-type disease, both of which may respond less favorably. At the molecular level, mutation frequencies differ across populations, including APC, ARID1A, KMT2A, and PIK3CA. The distribution of immunotherapy-relevant subtypes also varies: MSI and EBV-positive tumors, which are generally more responsive to ICIs, appear more frequent in some Asian cohorts, while CIN and genomically stable tumors are more common in some Western populations. The review further highlights differences in immune signaling and microbiome composition, suggesting that treatment response may emerge from a layered interaction between tumor genetics and host environment.
The authors argue that the key message is not simply that one group benefits more than another, but that gastric cancer immunotherapy is shaped by multiple overlapping determinants. Population-level differences in somatic mutations, molecular subtype composition, tumor immunity, and microbial exposure may all contribute to treatment variability. Understanding these mechanisms, they suggest, could help identify better biomarkers and guide more individualized treatment decisions for diverse patient populations.
The review points toward a more tailored future for gastric cancer care. Instead of treating ethnicity or geography as background variables, future trials may need to incorporate them into study design, biomarker analysis, and therapeutic decision-making. The authors also call for deeper translational work integrating genomics, immune profiling, and microbiome research, as well as model systems such as organoids and patient-derived xenografts. For clinicians, the message is practical: the same regimen may not produce the same benefit in every population. For researchers, the study offers a roadmap for building more precise and globally relevant immunotherapy strategies.
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References
DOI
10.20892/j.issn.2095-3941.2025.0398
Original Source URL
https://doi.org/10.20892/j.issn.2095-3941.2025.0398
Funding information
This manuscript was funded by MSD China. This work was supported by grants from Non-communicable Chronic Diseases-National Science and Technology Major Project (Grant No. 2024ZD0520600).
About Cancer Biology & Medicine
Cancer Biology & Medicine (CBM) is a peer-reviewed open-access journal sponsored by China Anti-cancer Association (CACA) and Tianjin Medical University Cancer Institute & Hospital. The journal monthly provides innovative and significant information on biological basis of cancer, cancer microenvironment, translational cancer research, and all aspects of clinical cancer research. The journal also publishes significant perspectives on indigenous cancer types in China. The journal is indexed in SCOPUS, MEDLINE and SCI (IF 8.4, 5-year IF 6.7), with all full texts freely visible to clinicians and researchers all over the world