Immune Checkpoint Inhibitors in EBV-Associated Gastric Cancer: An International Multicenter Retrospective Analysis

Nearly new cases of gastric cancer occur globally each year 100 Tens of thousands of cases, with related deaths exceeding 65 Ten Thousand Cases，This disease has become a major public health issue that urgently needs to be addressed on a global scale.^[1]. Most patientsAlready confirmed at the time of diagnosisFor advanced stages, the five-year survival rate is only 6%^[2]。EB Virus-related gastric cancer (EBVaGC) accounts for approximately all gastric cancer cases 9%, with unique immunophenotypic characteristics^[3]。

Previous studies have shown that immune checkpoint inhibitors (ICI) Treatment EBVaGC Objective Response Rate (ORR）In15%～100%, butRelated ResearchLimited by the small sample size,PatientSurvival outcome data remain unclear.^[4-6]. To further verifyEBVaGC Efficacy of Immunotherapy andExplore More EconomicalClinical DiagnosisMethod，2025 YearASCO A study presented at the meeting^[7]Based on Global 9 Data from a national tertiary cancer center clarified EBVaGC Patient Acceptance ICI Real-world treatment efficacy, assessed by next-generation sequencing (NGS) Substitute EBV Little EncodingRNA（EBER) In Situ Hybridization (ISH) The feasibility of using it as the gold standard for diagnosis, and identified ICI Sensitivity EBVaGC Molecular Characteristics。"DXY Oncology Time"Key Points of the Study，In order to provide guidance for clinical practice.

Through MSK-IMPACT AndCaris Life Sciences Two independent cohortsNGS TestingEBV Virus Sequence, and evaluate its association withEBER-ISH Consistency of test results. Retrospective data were collected from locally confirmed metastatic cases.EBVaGC Patient (Global Cohort)。The patients were divided into two groups, one group received onlyICI Treatment, another group receivedICI Combination chemotherapy; Further stratified according to the line of treatment, divided into first-line treatment (1L) with second-line and above treatments (2L+）。Progression-Free Survival (PFS) and overall survival (OS) AdoptKaplan-Meier Method for analysis.FromCaris Survival analysis and transcriptome-derived immune signature evaluation were performed on the parallel clinical genomics cohort of the Precision Oncology Alliance.Caris Cohort).EBVaGC Patient's NoteProgrammed Death Ligand1（PD-L1) Combined Positive Score (CPS) Stratified as< 5 Group &≥ 5 Two groups,MakeUseMann-Whitney U Inspection,t Test or Chi-square testComeComparison of molecular characteristics between groups (RNATPM Value, Immunohistochemistry Positive Percentage,DNA Amplification Frequency andDNA Missing Frequencyetc.) The difference.

This study included91 Example AcceptanceICI Metastatic TreatmentGC Patient, median age62 Years,91% Male, patient from the United States (n = 15), Europe (n = 5) and Asia (n = 71）。97% Patients receivingICI During treatmentECOG Physical Status (ECOG PS) Score ≤1 Points,69% PatientsPD-L1 CPS Score ≥5(Table1）。

InMSK-IMPACT And Caris In the queue,NGS WithEBER-ISH Test ResultsShowed high consistency, positive coincidence rate 98%，Negative Concordance Rate 99.9%(Table2）。

Table2 NGS WithEBER-ISH Test results inMSK AndCaris Consistency Comparison in the Cohort

Accept1L Chemotherapy Combined WithICI Treatment42 The patient example reached49% TheORR(Including complete remission and partial remission) (Table3), medianPFS Harmony MedianOS Respectively8.3 Months and38 Months (Fig.1）。1L And2L+ Simple ICI The treatment groups all showed approximately49% TheORR(Table3). In2L SimpleICI In the treatment population,PD-L1 CPS < 5 AndPD-L1 CPS ≥ 5 Median of SubgroupsPFS Respectively are3.0 Monthsvs 6.6 Months (Fig.1）。

Table3 Investigator-AssessedORR(Global Cohort)

Figure1 EBVaGC The patient received anti-PD-1/PD-L1 Clinical Efficacy of Treatment (Global Cohort)

Caris The genomic map of the cohort shows that cancers include esophageal cancer, esophagogastric junction cancer, and gastric adenocarcinoma. The molecular subtyping criteria include microsatellite status and human epidermal growth factor receptor.2（HER2) andEBV Expression status, etc. Different types of gastric cancer are associated with varying frequencies of pathogenic or likely pathogenic gene mutations, such asMMRd/MSI-H(Mismatch Repair Gene Deficiency/High Microsatellite Instability (MSI-H) Type Gastric CancerARID1A Gene Mutation FrequencyFor77.00%, andHER2 Positive Gastric CancerTP53 Mutation FrequencyUp to93.92%。TP53 InEBV Higher levels were also observed in negative gastric cancer.Mutation Frequency（72.74%). InEBVaGC In China,PIK3CA AndARID1A Mutation FrequencyEquivalent (Fig.2）。

Figure2 Gastric Cancer Genomic Atlas (Caris Cohort)

Data shows,InCaris In the cohort,EBVaGC Patient PopulationPD-L1 CPS ≥ 5 TheSubgroupBest prognosis, medianOS Reach21.0 Months (95%CI：15.3-36.8), significantly superior toEBVaGC ChinaPD-L1 CPS < 5 Group17.0 Months (95%CI：3.2-23.1) andNon-EBVaGC The patient's appointment13 Months (regardlessPD-L1 Status). InEBVaGC PatientIn China,PD-L1 High expression (CPS ≥ 5) The survival period of the low-expression group was prolonged compared to the4 Months(Figure3）, indicatingPD-L1 Expressed inEBVaGC Has clear prognostic stratification value in China. AndEBV Negative patients regardlessPD-L1 Expression level, medianOS Maintained at13 About months, indicatingEBV Positive status may be a factor influencingICI EfficacyThe key factor.

Figure3 According toEBV AndPD-L1 Overall Survival in Stratified Analysis (Caris Cohort)

InCaris In the queue,EBVaGC GroupInterferon-γ（IFN-γ）The score was significantly higher than other subtypes (q < 0.0001），CD8+ T Cell,B Cells and dendritic cells (DCs) Infiltration enhancement, cancer-associated fibroblasts (CAFs) Decrease. InEBVaGC In China,PD-L1 CPS ≥ 5 Subgroup-specific characteristics arePLA2G2D AndCSAG3 High gene expression.MTAP、CDKN2A Gene deletion occurs inPD-L1 CPS < 5 Group is more common (Fig.4）。

Figure4 EBV Positive Immune Microenvironment (Caris Cohort)

The study confirmed,NGS Can be accurately identifiedEBVaGC, thereby eliminating the need for expensiveEBER-ISH Testing. Whether combined with chemotherapy or not,ICI All can provideEBVaGC Patients bring higherORR。Versus Non-EBVaGC Compared with patients,EBVaGC Median patientOS Significantly prolonged, which may be related to the implementation rate of conversion surgery and regional differences.EBVaGC There is immune heterogeneity,PD-L1 CPS ≥ 5 Can effectively screenICI Benefiting Population. Compared with other molecular subtypes of gastric cancer,EBVaGC The most significantIFN-γ Signal Characteristics, whose tumor microenvironment is manifested as:CD8+ T Cell,B Cells and DCs Enhanced infiltration and CAFs Reduce.MTAP And CDKN2A Gene Deletion inPD-L1 More common in tumors with low expression.

EBVaGC Unique Molecular CharacteristicsClarified the tumorAnd the Immune SystemOfClose Interaction.EBVaGC Common DisplayTumor InfiltrationDense infiltration of lymphocytes, which is associated withVirusRelated to the ability of over-activating cellular immune responses^[8]。At the same time, its genomeCommonAppearPD-L1 And PD-L2 Copy number amplification, through activation PD-1 Approaches to Inhibit Immune Checkpoints, therebyInduce Immune Tolerance^[9]。EBV EncodedMaturemicroRNA YesDirect and indirect upregulation PD-L1 Expression, promoting tumor immune escape^[10]。The Cancer Genome Atlas (TCGA) Gastric Cancer CohortData further shows,EBVaGC The immune checkpoint pathway (such asPD-1/CTLA-4) expression levels were significantly higher than other gastric cancer subtypes^[9]。

Despite ample justification ICI In EBVaGC The efficacy of, but EBVaGC Only accounts for GC No10%, inAdvancedGC The proportion in China is higherLow,Therefore, recruiting enough EBVaGC Patients are relatively difficult, currentlyThe specific evidence for immunotherapy trials in this population is limited.

Statement:This material is supported by AstraZeneca and is for reference by healthcare professionals only.

Article Approval Number:CN-164683`, valid until `2026-07-21

Content Review: Kiki

Project Review: Liu Ruizi