Anti-PD-1 plus anti-angiogenesis combined with chemotherapy in patients with HER2-negative advanced or metastatic gastric cancer: a multi-institutional retrospective study

BACKGROUND: Immunotherapy plus chemotherapy have been confirmed to be effective in treating advanced or metastatic gastric cancer (GC). Anti- programmed death-1 (PD-1) plus antiangiogenic agents have shown promising activity and tolerant toxicity in subsequent therapy of late-stage gastric cancer. The aim of this study was to assess the efficacy and safety of anti-PD-1 plus anti-angiogenic agents and chemotherapy in advanced or metastatic GC and to explore the potential biomarkers associated with response. METHODS: We retrospectively reviewed thirty human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic GC patients who received PD-1 plus anti-angiogenic drugs and chemotherapy. Conversion therapy was defined when the patients could undergo resection post combination therapy. Clinical data were retrieved from medical records. We conducted exploratory biomarker analysis of baseline gene mutations and tumor mutation burden (TMB) using the next-generation sequencing (NGS), PD-L1 by immunohistochemistry (IHC), and the tumor immune microenvironment (TIME) by multiplex immunofluorescence. RESULTS: A total of 30 patients received anti-PD-1plus anti-angiogenic drugs and chemotherapy during the study period. The objective response rate (ORR) was 76.7% [95% confidence interval (CI): 57.7–90.1%] and disease control rate (DCR) was 86.7% (95% CI: 69.3–96.2%). A total of 11 patients (36.7%) achieved conversion therapy and underwent surgery. The R0 resection rate was 90.9%. Of the 11 patients, 9 (81.8%) responded to the treatment, 1 with a pathological complete response (pCR) and 8 with a major pathological response (MPR). No adverse events of grade 3 or higher occurred. Neither PD-L1 expression nor TMB was significantly correlated with treatment response. Analysis of TIME revealed that the fraction of CD8(+) T cell in the invasive margin was higher in responders than non-responders before treatment. TAM2 in the tumor center and CD8(+) T cell in the invasive margin was significantly increased after combination therapy, which suggested that combination therapy promoted infiltration of CD8(+) T cells, thereby exerting an antitumor effect. CONCLUSIONS: Immunotherapy plus anti-angiogenic drugs and chemotherapy is a promising treatment strategy for advanced or metastatic GC patients. Tumor infiltration CD8(+) T cells may serve as potential predictive biomarker.