Neoadjuvant Dual Immunotherapy in T4 Locally Advanced Deficient Mismatch Repair Gastric or Esophagogastric Junction ( EGJ ) Adenocarcinoma

ABSTRACT Although combining programmed cell death protein 1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) and cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) inhibitors in neoadjuvant therapy is effective for deficient mismatch repair (dMMR) or microsatellite instability‐high (MSI‐H) gastric or esophagogastric junction (EGJ) adenocarcinoma, few T4 stage patients have been studied. The effectiveness and safety of this dual immunotherapy for T4 locally advanced dMMR/MSI‐H gastric/EGJ adenocarcinoma is largely unknown. Patients with T4 locally advanced dMMR/MSI‐H gastric/EGJ adenocarcinoma treated with dual immune checkpoint inhibitors as neoadjuvant therapy were identified from a prospectively maintained gastric/EGJ adenocarcinoma database. The primary endpoint was the pathological complete response (pCR) rate. Twenty‐three patients were included in this study. Of these, 22 (95.7%) completed dual immunotherapy before surgery, while one missed a dose due to immune‐related hypophysitis. Sixteen patients (69.6%) underwent surgery, achieving a 100% R0 resection rate. The pCR rate was 81.3% (95% confidence interval (CI): 57.0%–93.4%) and the major pathological response (MPR) rate was 93.8%. Seven patients did not have surgery; five of them, with complete clinical response, opted for a “watch‐and‐wait” strategy. The event‐free survival rate was 95.5% at a median follow‐up of 22.1 months, with manageable adverse events. Dual immunotherapy shows promise for T4 locally advanced dMMR/MSI‐H gastric/EGJ adenocarcinoma, and the “watch‐and‐wait” strategy deserves further study in dMMR/MSI‐H cases. Larger studies are needed to confirm these results and optimize treatment.