Efficacy and safety of neoadjuvant chemoradiotherapy combined with immunotherapy for locally advanced esophagogastric junction or gastric cancer: a systematic review and meta analysis.

Background: With significant progress made in immunotherapy for locally advanced and metastatic gastroesophageal junction or gastric cancer (EGJ/GC), multiple studies have been initiated on neoadjuvant chemoradiotherapy (nCRT) combined with immune checkpoint inhibitors (nCRT+ICIs) for locally resectable EGJ/GC. Consequently, current clinical trials investigating nCRT+ICIs for locally advanced EGJ/GC were summarized within this study. A systematic review and meta-analysis were performed to evaluate the efficacy and safety of this combination therapy, with the objective of providing clinicians with robust, evidence-based treatment strategies and clinical references. Materials and methods: Relevant studies were retrieved from electronic databases including PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, ASCO, ESMO, and CNKI. Efficacy was evaluated based on the pathological complete response (pCR) rate, major pathological response (MPR) rate, downstaging and the R0 resection rate. Safety was assessed by the incidence of grade ≥3 treatment-related adverse events (TRAESs) and grade ≥3 immune-related adverse events (irAEs). All statistical analyses were performed using Stata version 15.0. Results: A total of 12 studies fulfilled the inclusion criteria for analysis. The pooled rates of pathological complete response (pCR), major pathological response (MPR), and R0 resection were found to be 29%, 52%, and 100%, respectively. The pooled T-stage downgrading rate was 51%. The N-stage downstaging rate was 73%, with all cases successfully downstaged to ypN0. The incidences of grade ≥3 TRAESs and irAEs were 47% and 6%, respectively. The pooled 2-year progression-free survival (PFS) rate was 65%, while the 1-year and 2-year overall survival (OS) rates were 91% and 74%, respectively. Subgroup analyses indicated pCR rates of 26% and 33% for the programmed death-ligand 1 (PD-L1) and programmed death-1 (PD-1) inhibitor subgroups, respectively. Comparable pCR rates of 29% were observed for both sequential and concurrent chemoradiotherapy combined with immunotherapy. Within the concurrent therapy subgroup, a higher pCR rate was achieved with PD-1 inhibitor-based regimens (36%) than with PD-L1 inhibitor-based regimens (25%), while a 29% pCR rate was demonstrated for PD-L1 inhibitor sequential therapy. Stratification by the PD-L1 combined positive score (CPS) yielded pCR rates of 22% for CPS <1, 23% for CPS 1-5, and 51% for CPS ≥5. Radiation dose stratification showed pooled pCR rates of 26% for doses <45Gy and 33% for doses ≥45Gy. Regional variations were observed, with Asian cohorts exhibiting a higher pCR rate (36%) than Western cohorts (26%). Conclusion: In locally advanced EGJ/GC, the combination of PD-1/PD-L1 inhibitors with nCRT demonstrates promising response rates and acceptable toxicity profiles. Notably, this regimen achieved pCR rate of 51% in patients with CPS ≥5. Furthermore, favorable outcomes were observed even in those with low CPS. This study is primarily based on phase II or single-arm data; therefore, these results remain preliminary. These findings require further validation in future large-scale randomized controlled trials (RCTs). Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024590688.