Efficacy of anti-PD-1/PD-L1 plus chemotherapy in treatment-naïve advanced HER2-negative gastric adenocarcinoma among different PD-L1 intervals: an updated meta-analysis and reconstructed individual patient-level data analysis

Abstract

Abstract Background Chemo-immunotherapy (CIT) has become the frontline therapy for advanced human epidermal growth factor receptor 2 (HER2)-negative gastric or gastro-esophageal junction adenocarcinoma (GEAC). However, emerging evidence suggests that clinical benefit is primarily derived from patients with a high combined positive score (CPS), whereas the efficacy of CIT among different CPS intervals remained unknown. Methods A systemic literature search was performed to screen for RCTs studying addition of PD-1/PD-L1 inhibitors to chemotherapy versus chemotherapy alone in metastatic GEAC with efficacy information across different CPS interval. Pooled analysis of hazard ratios (HRs) for overall survival (OS), progression free survival (PFS), odds ratios (ORs) for objective response rate (ORR) and heterogeneity analysis on treatment efficacy were performed in CPS < 1, 1 ~ 4, 5 ~ 9, ≥10 subgroups. Results The analysis showed that adding programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors to ChT significantly improved overall survival (OS) in the CPS ≥ 10 subgroup (hazard ratio [HR], 0.67 [95%CI 0.61–0.73]), but not in the CPS < 1 or 5–9 subgroups; only a marginal benefit was observed in the CPS 1–4 subgroup. CPS ≥ 10 vs <10 presented the strongest interaction effect between CPS and the efficacy of adding PD-1/PD-L1 inhibitors to ChT ( P interaction < 0.0001). Additionally, CIT significantly improved the progression-free survival (PFS) and objective response rate (ORR) in both CPS-low (CPS < 1: HR, 0.85 [95%CI 0.72–1.00]; odds ratio [OR], 1.41 [95%CI 1.02–1.96]) and CPS-high (CPS ≥ 10: HR, 0.64 [95%CI 0.58–0.70]; OR, 1.87 [95%CI 1.50–2.33]) subgroups versus ChT alone. Conclusions CPS ≥ 10 defines a subgroup deriving the greatest benefit from CIT, supporting its use as a clinically informative threshold for PD-1 inhibitor therapy in advanced GEAC. Nevertheless, patients with CPS < 10 may still gain benefit from CIT when tumor shrinkage is the primary treatment objective.