Immunotherapy combined with chemotherapy as first-line treatment for HER2-negative advanced gastric or gastroesophageal junction cancer: systematic review and Bayesian network meta-analysis based on specific PD-L1 expression levels

Gastric/gastroesophageal junction cancer (G/GEJC) is a major global health concern. HER2-negative advanced cases, which are common, have a poor prognosis and high peritoneal metastasis rates. First-line chemotherapy has limitations, while immunotherapy combined with chemotherapy shows promise, the optimal regimen for patients with different PD-L1 expression levels remains unclear. We conducted a systematic review and Bayesian network meta - analysis by searching PubMed, Embase, Cochrane Library, and Web of Science databases. Eight RCTs involving 7619 patients and 7 immunotherapy-chemotherapy regimens were included. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and grade ≥ 3 adverse events (AEs). This analysis evaluated the efficacy and safety of various first-line immunotherapy-combination chemotherapy regimens for patients with HER2-negative advanced G/GEJC. Additionally, we assessed treatment efficacy across different PD-L1 expression subgroups.This study was registered in the Prospective Register of Systematic Reviews (CRD420251028737). Conventional meta-analysis showed that compared with chemotherapy alone, immunotherapy - chemotherapy significantly improved OS (HR = 0.79, 95% CI: 0.74–0.84), PFS (HR = 0.72, 95% CI: 0.68–0.77), and ORR (RR = 1.61, 95% CI: 1.45–1.80) in HER2-negative advanced G/GEJC patients. However, it also led to a higher incidence of grade ≥ 3 adverse events (AEs, RR = 1.18, 95% CI: 1.13–1.23). Subgroup analysis revealed that in patients with PD - L1 expression ≥ 1%, ≥ 5%, and ≥ 10%, this combination therapy significantly improved OS and PFS, with greater benefits at higher combined positive scores (CPS). Network meta - analysis indicated that for PD-L1 unselected patients, cadonilimab combined with chemotherapy was superior in OS, PFS, and ORR. In PD - L1 ≥ 1% patients, pembrolizumab plus chemotherapy had the best OS; in PD-L1 ≥ 5% patients, cadonilimab plus chemotherapy was optimal for OS and nivolumab plus chemotherapy for PFS; in PD-L1 ≥ 10% patients, sugemalimab plus chemotherapy was most effective for both OS and PFS. In conclusion, these findings support immunotherapy-combination chemotherapy as a superior first-line strategy for HER2-negative advanced G/GEJC. Different optimal regimens can be selected based on PD-L1 expression levels, providing evidence-based guidance for clinical decision-making.