Neoadjuvant immunotherapy Versus Surgery +/− Chemotherapy in High Resectable Gastroesophageal Adenocarcinoma

This study focused on comparing neoadjuvant immunotherapy using immune checkpoint inhibitors (ICIs) with surgery and/or chemotherapy in patients with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) resectable gastroesophageal adenocarcinoma (GEA). These tumors are known to respond poorly to chemotherapy but are highly immunogenic, making immunotherapy a promising approach.

The analysis included 197 patients divided into four groups: ICIs (49 patients), FLOT chemotherapy (27 patients), surgery alone (33 patients), and older chemotherapy regimens (88 patients). The study primarily assessed pathologic complete response (pCR) and major pathologic response (MPR) rates, alongside event-free survival (EFS) and overall survival (OS).

Key findings showed that neoadjuvant ICIs resulted in significantly better tumor responses compared to chemotherapy. Patients treated with ICIs achieved a pCR rate of 61.9% versus 3.7% with FLOT chemotherapy, and an MPR rate of 78.6% versus 10%. Additionally, ICIs reduced residual nodal disease (ypN+) to 14.3% compared to 37% with chemotherapy, indicating superior tumor downstaging.

Despite these impressive pathologic responses, survival outcomes (EFS and OS) were comparable between ICIs and surgery ± chemotherapy groups. At 36 months, EFS was 70.4% for ICIs versus 80.6% for surgery, and OS was 72.7% versus 90.4%. Patients with residual nodal disease (ypN+), advanced tumor stage (ypT4), or lack of pathologic response had worse survival outcomes.

This study highlights neoadjuvant immunotherapy as a highly effective strategy for dMMR/MSI-H GEA, offering profound tumor regression and reduced reliance on chemotherapy. These findings support the potential for organ-sparing or non-surgical treatment approaches, paving the way for immunotherapy-centered management in this patient subgroup.