Efficacy and safety of PD-1 inhibitors in combination with chemotherapy as first-line treatment for HER2-negative advanced gastric or gastroesophageal junction cancer across subgroups: A comprehensive systematic review and meta-analysis

Background: The advent of immune checkpoint inhibitors has introduced innovative therapeutic paradigms for the management of human epidermal growth factor receptor 2 (HER2)-negative advanced gastric or gastroesophageal junction cancer (GC/GEJC). However, the efficacy and safety of programmed cell death protein 1 (PD-1) inhibitors combined with chemotherapy versus chemotherapy alone in patients with HER2-negative advanced GC/GEJC remain contentious. The comparability among different subgroups is not fully understood, necessitating the identification of optimal patient demographics and the exploration of potential biomarkers. Methods: This study identified 6 Phase III randomized controlled trials evaluating the first-line treatment of HER2-negative GC/GEJC with PD-1 inhibitors in combination with chemotherapy. The primary endpoints include overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), assessed using hazard ratios (HR), relative risk, and their respective 95% confidence intervals (CI). Secondary outcomes are treatment-related adverse events and immune-related adverse events. Prespecified subgroups encompass microsatellite instability, programmed death-ligand 1 (PD-L1) combined positive score (CPS), age, gender, previous surgery, primary location, liver metastases, Eastern Cooperative Oncology Group performance status score, histological subtype, chemotherapy regimen, race, and PD-L1 expression in tumor cells. Results: Incorporating data from 6 randomized controlled trials, this analysis included 6294 adult patients with HER2-negative advanced GC/GEJC. The combined PD-1 inhibitor and chemotherapy regimen significantly improved OS ( HR  = 0.79, 95% CI [0.75, 0.84], P  < .00001) and PFS ( HR  = 0.75, 95% CI [0.70, 0.80], P  < .00001), along with enhancing the ORR (relative risk = 1.22, 95% CI [1.15, 1.29], P  < .00001). Subgroup analyses revealed benefits in OS, PFS, and ORR for patients with CPS ≥ 1, CPS ≥ 5, and CPS ≥ 10 when treated with first-line PD-1 inhibitors and chemotherapy, with higher PD-L1 expression levels correlating with greater efficacy. Furthermore, patients with high microsatellite instability exhibited a more pronounced extension in OS ( HR  = 0.35, 95% CI [0.21, 0.59], P  < .0001). However, factors such as age, gender, previous surgery, primary location, liver metastases, Eastern Cooperative Oncology Group performance status score, histological subtype, chemotherapy regimen, race, and PD-L1 expression in tumor cells were not predictive of an OS benefit from PD-1 inhibitors combined with chemotherapy over chemotherapy alone. Regarding safety, the PD-1 inhibitor and chemotherapy combination led to a higher incidence of immune-mediated adverse events, though there was no significant difference in adverse events leading to death. Conclusion: First-line treatment with PD-1 inhibitors combined with chemotherapy surpasses chemotherapy alone in efficacy for patients with HER2-negative advanced GC/GEJC, particularly in those with CPS ≥ 10 or high microsatellite instability, with tolerable adverse events.