Neoadjuvant CTLA-4/PD-(L)1 Blockade Versus Surgery +/- Chemotherapy in Deficient Mismatch Repair/Microsatellite...

Area of Science:

• Oncology
• Gastroenterology
• Immunotherapy

Background:

• Deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) resectable gastroesophageal adenocarcinoma (GEA) shows limited benefit from chemotherapy.
• Preoperative immune checkpoint inhibitors (ICIs) have shown promise in achieving major pathologic responses.

Purpose of the Study:

• To determine the optimal treatment strategy for resectable dMMR/MSI-H GEA.
• To compare neoadjuvant ICIs with standard chemotherapy (FLOT) and surgery alone.

Main Methods:

• A pooled analysis of individual patient data was conducted.
• Patients were stratified into groups receiving neoadjuvant dual CTLA-4/PD-(L)1 ICIs, perioperative FLOT, or surgery alone.
• Pathologic complete response (pCR), major pathologic response (MPR), event-free survival (EFS), and overall survival (OS) were primary and secondary endpoints.

Main Results:

• ICIs demonstrated significantly higher pCR (61.9% vs 3.7%) and MPR (78.6% vs 10%) compared to FLOT in resected patients.
• ICI treatment resulted in lower ypN+ (14.3% vs 37%) and ypT stage compared to FLOT.
• No significant differences in 36-month EFS and OS were observed between ICI and surgery alone groups.

Conclusions:

• Neoadjuvant ICIs significantly enhance pathologic response and downstaging in resectable dMMR/MSI-H GEA compared to FLOT.
• Comparable EFS/OS with ICIs to surgery alone supports their use, especially in high-risk disease.
• High pCR/MPR rates with ICIs suggest potential for organ-sparing or nonoperative management strategies.