Impact of Adding Immune Checkpoint Inhibitors to Neoadjuvant Chemotherapy on pCR and Tumor Downstaging in Resectable...

Background/Objectives: Despite standard perioperative chemotherapy, recurrence remains frequent in resectable gastric cancer (GC). We investigated the clinical impact of integrating immunotherapy into the neoadjuvant component of perioperative treatment, particularly on pathological complete response (pCR), in this setting. Methods: We conducted a systematic review and meta-analysis of phase II-III trials and real-world studies evaluating immune checkpoint inhibitors (ICIs) added to perioperative chemotherapy versus chemotherapy alone in resectable GC. Two independent reviewers screened PubMed and Scopus; review articles and single-arm studies were excluded. Pooled odds ratios (ORs) were estimated using random-effects models, and heterogeneity was assessed with the I² statistic. Overall, six studies including 2890 patients were analyzed. Results: The addition of ICIs significantly enhanced tumor regression, increasing ypT0-T2 rates (OR 1.61, 95% CI 1.11-2.33; p = 0.012) and reducing ypT3-T4 residual disease (OR 0.62, 95% CI 0.44-0.87; p = 0.0051). A favorable trend toward nodal downstaging was observed (ypN0-1 OR 1.57; ypN2-3 OR 0.60), although these differences did not reach statistical significance. Notably, pathological complete response (pCR) rates more than tripled with chemo-immunotherapy (OR 3.39, 95% CI 2.21-5.20; I² = 38.9%; p < 0.0001). The magnitude of benefit was particularly striking in PD-L1-positive tumors (OR 3.26; p < 0.0001). pCR improvement was strongest with PD-1 inhibitors (OR 4.10; p < 0.0001), while remaining significant with PD-L1 inhibitors (OR 2.62; p < 0.0001). Treatment benefit was consistent across age groups (<65 and ≥65 years) and performance status (ECOG PS 0-1). R0 resection rates were not significantly different. Conclusions: Overall, the addition of ICIs to perioperative chemotherapy substantially increases pathological response and tumor downstaging in resectable GC. These findings support further investigation of immunotherapy-based perioperative strategies. However, the present evidence is mainly driven by pathological endpoints, and the role of pCR as a surrogate for long-term survival in gastric cancer remains uncertain. Therefore, mature survival data are needed before definitive conclusions regarding clinical practice can be drawn.