Neoadjuvant CTLA-4/PD-(L)1 Blockade Versus Surgery +/- Chemotherapy in Deficient Mismatch Repair/Microsatellite Instability-High Resectable Gastroesophageal Adenocarcinoma: Individual Patient Data Pooled Analysis

Abstract

Purpose: Patients with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) resectable gastroesophageal adenocarcinoma (GEA) have better survival after surgery and scant/no benefit from chemotherapy. Preoperative immune checkpoint inhibitors (ICIs) demonstrated a high proportion of major complete pathologic response, possibly allowing chemotherapy/surgery-free approaches.

Methods: Individual patient data pooled analysis was performed to determine an optimal strategy for resectable dMMR/MSI-H GEA. Patients were stratified across four groups: neoadjuvant dual CTLA-4/PD-(L)1 ICIs with or without surgery, perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) and surgery, and surgery alone or with older perioperative/adjuvant chemotherapy regimens. Primary end points were pathologic complete and major complete pathologic response proportion (pathologic complete response [pCR], tumor regression grade [TRG]1a, major pathologic response [MPR], TRG1a/b Becker criteria) in resected patients. Secondary end points were event-free survival (EFS) and overall survival (OS) in the overall population.

Results: Among 197 patients, 49 received ICIs, 27 FLOT, 33 surgery alone, and 88 older chemotherapy regimens. Among 69 patients who underwent surgery after ICIs or FLOT, ICIs demonstrated significantly higher pathologic response versus FLOT (pCR, 61.9% v 3.7%; odds ratio [OR], 54.8; P = .002; MPR, 78.6% v 10%; OR, 39.3; P < .001) and lower ypN+ (14.3% v 37%; OR, 4.2; P = .015) and ypT (OR, 16.4; P < .001) stage. No significant differences in EFS/OS were observed (the 36-month EFS and OS were 70.4% v 80.6% and 72.7% v 90.4% with ICI v surgery alone). Residual nodal disease (ypN+) or ypT4 status after neoadjuvant ICIs or FLOT and nonpathologic response status were associated with inferior progression-free survival/OS.

Conclusion: In resectable dMMR/MSI-H GEA, neoadjuvant ICIs significantly increase pathologic response and downstaging versus FLOT, with comparable EFS/OS with surgery with or without chemotherapy. The higher proportion of ypN0 and lack of ypT4 after neoadjuvant ICIs versus FLOT should drive preoperative treatment choices in clinical high-risk disease. The high proportion of pCR/MPR with ICIs provides rationale for exploring organ-sparing surgery or nonoperative management.