A meta-analysis of perioperative immunotherapy modalities in patients with dMMR/MSI-H gastric and gastroesophageal junction adenocarcinoma.

Abstract

e16127 Background: Immunotherapy for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) gastric/gastroesophageal junction (G/GEJ) adenocarcinoma lacks large-scale clinical evidence, especially in neoadjuvant therapy. Here, we used meta-analysis to investigate the efficacy and safety of different immunotherapy-based regimens in neoadjuvant treatment of G/GEJ cancer, and explored the relationship between effective regimens and tumor characteristics by online datasets. Methods: Following PRISMA guidelines, we searched databases and conference abstracts, including 23 clinical trials of neoadjuvant immune checkpoint inhibitors (ICIs)-based therapy for resectable dMMR/MSI-H G/GEJ cancer. We performed meta-analysis using STATA18 software. Tumor mutations were analyzed via TCGA somatic mutation data with maftools (R package), including TMB calculation and subclonal/CNV/MHC gene analysis. Tumor immune microenvironment was assessed using GEO scRNA-seq data via Cell Ranger/Seurat/Harmony processing, cell type annotation and MHC-I/II molecule analysis in tumor cells. Results: Meta-analysis showed ICIs-based therapies had significantly higher pathological complete response (pCR = 0.68) and major pathological response (MPR = 0.99) than chemotherapy alone(pCR = 0.08, MPR = 0.01). ICIs combined with chemotherapy achieved the best efficacy followed by dual ICIs, with tolerable adverse events. The R0 resection rate was approximately 100% for all regimens, while ICIs combined with chemotherapy demonstrated the highest downstaging rate. Asian populations benefited more from single-agent ICIs while Europeans had better responses to dual ICIs. Results by analyzing TCGA database revealed dMMR/MSI-H GC had higher tumor mutational burden, subclonal mutations, copy number variations and expression of MHC-I/II moleculars than dMMR/MSI-H colorectal cancer and microsatellite stability GC. Further, single-cell sequence analysis showed that the infiltration of CD8 + T and CD4 + T cells was higher in dMMR/MSI-H GC, indicating that dMMR/MSI-H GC possessed high tumor heterogeneity and immunogenicity. Conclusions: ICIs combined with chemotherapy is the optimal neoadjuvant regimen for dMMR/MSI-H G/GEJ cancer with manageable toxicity, followed by dual ICIs. Single-agent ICIs are more beneficial for Asians. Tumor heterogeneity may contribute to the superior efficacy of combination therapy, providing evidence for clinical regimen selection.