Efficacy and safety of PD-1 inhibitor plus chemotherapy vs chemotherapy alone in advanced gastric cancer patients with low or negative PD-L1 expression.

Abstract

4041 Background: Advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma remains a major global health challenge with limited treatment options and poor prognosis in metastatic or unresectable disease. Immune checkpoint inhibitors targeting the programmed death-1 (PD-1) pathway, when combined with standard chemotherapy, have improved outcomes in overall populations, as shown in pivotal trials such as CheckMate-649 and KEYNOTE-859. However, efficacy is strongly influenced by tumor PD-L1 expression, with patients exhibiting low or negative PD-L1 expression (combined positive score [CPS] <1 or <5, or tumor area positivity [TAP] <5%) derive less pronounced benefit. Subgroup analyses from ORIENT-16 and RATIONALE-305 show heterogeneous results, leaving uncertainty regarding the benefit of PD-1 inhibitors in this subgroup. We aimed to evaluate the efficacy and safety of first-line PD-1 inhibitor–chemotherapy combinations versus chemotherapy alone in this clinically important population. Methods: A systematic search of PubMed/MEDLINE, Embase, Cochrane Library, Scopus, ClinicalTrials.gov, and major oncology conferences was conducted through January 16, 2026. We included Phase III randomized controlled trials comparing PD-1 inhibitor plus chemotherapy with chemotherapy alone in adults with treatment-naïve advanced gastric or GEJ adenocarcinoma and low/negative PD-L1 expression (CPS <1, <5, or TAP <5%). Meta-analyses were conducted using RevMan 5.4 with the generic inverse variance method for time-to-event outcomes (HR) and Mantel–Haenszel method for dichotomous outcomes (RR). Heterogeneity was assessed using I². Primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes included objective response rate and safety. Results: Four Phase III RCTs (CheckMate-649, KEYNOTE-859, ORIENT-16, RATIONALE-305) comprising 4,761 patients were included. Subgroup data from patients with low/negative PD-L1 expression were analyzed. PD-1 inhibitors did not improve OS (HR 0.92, 95% CI 0.81–1.03, P=0.16; I²=0%) or PFS (HR 0.84, 95% CI 0.70–1.02, P=0.08; I²=47%). Results were consistent across CPS and TAP methods. Toxicity was significantly increased, with higher grade ≥3 adverse events (RR 1.48, P<0.001) and immune-related adverse events (any grade RR 2.80; grade ≥3 RR 4.30). Conclusions: In advanced gastric/GEJ adenocarcinoma with low/negative PD-L1 expression, first-line PD-1 inhibitor plus chemotherapy provides no survival benefit and substantially increases toxicity. These findings support biomarker-guided treatment selection and highlight the need for alternative therapeutic strategies.