Efficacy and safety of PD-1/PD-L1 inhibitors combined with chemotherapy in patients with advanced gastric or gastro-esophageal junction cancer: A systematic review and meta-analysis

Although the efficacy and safety of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitor combined with chemotherapy vs. chemotherapy alone has been analyzed, there have been no in-depth studies on the outcomes of patients with PD-L1 positive advanced gastric or gastro-esophageal junction cancer patients (GC/GEJC). This systematic review and meta-analysis focused on comparing the efficacy and safety of PD-1/PD-L1 inhibitors vs. PD-1/PD-L1 inhibitors combined with chemotherapy vs. chemotherapy in PD-L1 positive advanced GC/GEJC patients, aiming to provide more precise guidance for the clinical treatment of GC/GEJC. In this meta-analysis, PubMed, Embase, and Cochrane Library were searched from the establishment of the database till June 2022. Randomized controlled trials (RCTs) in which control patients underwent chemotherapy and experimental group patients underwent PD-1/PD-L1 inhibitors or PD-1/PD-L1 inhibitors combined with chemotherapy were included in this investigation. Investigations without complete information, studies from which information could not be extracted, duplicate articles, animal studies, review articles, and systematic reviews were excluded. The pooled results suggested that chemotherapy combined with immunotherapy prolonged overall survival (OS) in patients with advanced GC/GEJC, while progression free-survival (PFS) with PD-1/PD-L1 inhibitors alone or in combination with chemotherapy were all improved compared with chemotherapy alone. However, PD-1/PD-L1 inhibitors did not significantly increase objective response rates (ORR) in PD-L1-positive patients compared with chemotherapy, but in combination with chemotherapy, they did improve ORR. The pooled results also showed that patients treated with PD-1/PD-L1 inhibitors had higher stable disease (SD) and progressive disease (PD) rates compared to chemotherapy in PD-L1-positive patients. Additionally, in PD-L1-positive patients, PD-1/PD-L1 inhibitors alone or combined with chemotherapy increased OS compared with chemotherapy alone. However, PD-1/PD-L1 inhibitors only prolonged PFS compared with chemotherapy alone in patients with a combined positive score (CPS; 100% of cells were required to be positively stained) for PD-L1, but when combined with chemotherapy, OS and PFS were prolonged in all PD-L1-positive patients compared with chemotherapy alone. Finally, the pooled results showed that the incidence of adverse events of PD-1/PD-L1 inhibitors in PD-L1-zpositive patients was significantly lower than that in patients treated with chemotherapy alone. In conclusion, single agent of PD-1/PD-L1 inhibitor alone or combined with chemotherapy significantly prolongs the survival of patients compared with chemotherapy alone, with fewer adverse effects. However, the degree of CPS may affect efficacy, thus further investigation is required.