Network meta-analysis of first-line therapies for unresectable HER2-negative gastric/gastroesophageal junction adenocarcinoma: Efficacy and safety of novel combinations versus standard chemoimmunotherapy.

Abstract

e16045 Background: For patients with unresectable HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma, first-line chemotherapy alone provides limited benefit. Combining novel agents—including immune checkpoint inhibitors (ICIs), adoptive cell therapy (ACT), and targeted therapies—with chemotherapy may improve outcomes. This network meta-analysis (PROSPERO: CRD420251058622) comprehensively compares the efficacy and safety of these emerging first-line regimens. Methods: We systematically searched PubMed, EMBASE, the Cochrane Library, and conference abstracts (Jan 2013–Aug 2025) for randomized controlled trials evaluating first-line systemic treatments. A frequentist random-effects network meta-analysis was performed to synthesize evidence on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs). Results: Twenty-nine trials (14,318 patients, 18 regimens) were included. ACT combined with triplet chemotherapy ranked highest for improving PFS (P-score: 0.94) and ORR (SUCRA: 91.1), and showed a significant OS benefit over doublet chemotherapy (HR 1.49, 95% CI 1.06–2.09). Adding a PD-1 inhibitor to doublet chemotherapy significantly improved both OS and PFS. Bispecific antibodies demonstrated considerable efficacy: PD-1/CTLA-4 bispecific antibody plus doublet chemotherapy ranked first for OS (P-score: 0.86) and third for PFS (P-score: 0.88); PD-L1/TGF-β bispecific antibody plus doublet chemotherapy ranked second for OS (P-score: 0.86) and third for ORR (SUCRA: 82.9). MET inhibitor plus triplet chemotherapy ranked second for PFS (P-score: 0.89) and ORR (SUCRA: 87.6) and third for OS (P-score: 0.86). Other targeted agents (anti-EGFR, anti-VEGF, TKIs) combined with chemotherapy did not confer significant survival advantages. All chemotherapy-based combinations increased the risk of grade ≥3 TRAEs versus doublet chemotherapy, with safety profiles consistent with known toxicity patterns and no new safety signals. Conclusions: Beyond standard chemoimmunotherapy, ACT-based combinations and bispecific antibody regimens show meaningful survival benefits with acceptable toxicity. This is the first network meta-analysis to evaluate the clinical applicability of ACT and bispecific antibodies in the first-line setting for advanced gastric cancer. These findings support the consideration of novel immunotherapeutic combinations and may inform future trial design.