Application Progress of Immune Checkpoint Inhibitors in the Immunotherapy of Metastatic/Locally Advanced Esophagogastric Adenocarcinoma postprint

Abstract: Adenocarcinoma of the gastroesophageal junction (GEJ) has a poor prognosis, and conventional chemotherapy and targeted therapy have limited efficacy. Immune checkpoint inhibitors (ICIs), which block pathways such as PD-1/PD-L1, have brought breakthroughs in the treatment of advanced GEJ adenocarcinoma. However, their clinical application still faces challenges including heterogeneous response, toxicity management, and drug resistance. This article systematically reviews the latest advances of ICIs in metastatic/locally advanced GEJ adenocarcinoma. Monotherapy (e.g., nivolumab, pembrolizumab) has become the standard later-line option, but its efficacy is dependent on biomarkers such as PD-L1 combined positive score (CPS) and microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) status. Combination therapy is the current core strategy in current clinical practice. ICIs combined with chemotherapy (e.g., as demonstrated in the CheckMate-649 and KEYNOTE-811 trials) have significantly improved survival in first-line HER2-negative and HER2-positive patients, establishing a new standard of care for advanced GEJ adenocarcinoma. ICIs combined with anti-angiogenic agents (e.g., apatinib) and novel targeted drugs (e.g., anti-CLDN18.2 and anti-FGFR2b antibodies) have shown promising efficacy in GEJ adenocarcinoma, offering new directions for later-line treatment. Dual immunotherapy (e.g., nivolumab combined with ipilimumab) demonstrates high pathological complete response (pCR) rates in dMMR/MSI-H populations, although its toxicity requires careful attention. Biomarkers [e.g., PD-L1 CPS, MSI-H/dMMR, tumor mutational burden(TMB)] are crucial for predicting efficacy and optimizing patient stratification; future efforts need to focus on constructing combinatorial models to enhance predictive accuracy. Combination therapy is the mainstream direction for ICI treatment in GEJ adenocarcinoma. Future strategies should involve exploring multi-omics-guided personalized approaches, developing novel drug combinations, and optimizing the biomarker system to overcome resistance, balance efficacy and toxicity, and ultimately achieve precision therapy.