First-line PD-1 inhibitor plus chemotherapy improves outcomes in advanced gastric cancer and correlates with specific biomarkers in a real-world cohort.

backgroundImmune checkpoint inhibitors (ICIs) have become the main treatment method for human epidermal growth factor receptor 2 (HER2)-negative advanced gastric cancer (GC). This study analyzed from real-world data the efficacy of first-line programmed death 1 (PD-1) inhibitors combined with chemotherapy in patients with advanced GC. MATERIALS AND

methodsWe collected data from GC patients who were admitted to Cancer Hospital of Chinese Academy of Medical Sciences and Peking Union Medical College from November 2020 to April 2024. The clinical TNM stage was stage IV. All patients were HER2-negative with proficient mismatch repair. These patients were treated with SOX chemotherapy combined with a PD-1 inhibitor. Partial blood samples were collected from prospective enrolled cases for exploratory analysis.

resultsWe included 190 patients with GC with a histological diagnosis of adenocarcinoma. As of December 31, 2025, the median follow-up was 18.00 (95% confidence interval [CI] 10.00–25.62 months). Of the 190 patients enrolled, 174 had measurable lesions. 99 patients achieved a partial response (PR), 8 achieved a complete response (CR), and 61 had stable disease (SD) as their best overall response. The objective response rate (ORR) and disease control rate (DCR) were 61.9% (95% CI: 48.8–73.4) and 96.8% (95% CI 89.0–99.6), respectively. Progression free survival (PFS) data were obtained in 180 cases and overall survival (OS) data in 165 cases. The median PFS and OS were 8.2 months (95% CI 7.2–10.0) and 20.8 months (95% CI 17.1–23). Risk factor analysis found that the overall expression level of HER2 was significantly associated with ORR. In survival analysis, different expression levels of HER2 were significantly correlated with PFS. Although the difference was not statistically significant, the OS of patients with HER2 expression level of “2” tended to be longer than that of patients with “1+"expression. We collected baseline blood samples of 62 patients to test for circulating tumor DNA (ctDNA), and the data passed quality control. The analysis results suggested that PFS was significantly shorter in patients with copy number variants (CNV) of Exostosin 1 (EXT1) compared to wild-type EXT1 patients (p = 0.00046). OS was significantly shorter in patients with single nucleotide variant (SNV) in STK11 mutations than in patients with wild-type STK11 (p = 0.0083). OS was significantly shorter in patients with CNVs in MYC and EXT1 than in patients with wild-type MYC (p < 0.0001) and EXT1 (p < 0.0001) patients.

conclusionsThis real-world study describes the clinical outcomes of patients with advanced GC receiving first-line PD-1 inhibitor combined with chemotherapy. The findings suggest that HER2 expression levels, even within the HER2-negative subgroup, may have prognostic relevance and warrant further investigation. In addition, circulating tumor DNA analysis showed potential as a predictor of survival in this cohort, though its clinical utility requires validation in future prospective studies.