Immune checkpoint inhibitors plus chemotherapy versus chemotherapy alone as first-line therapy for advanced gastric and esophageal cancers: A systematic review and meta-analysis

Esophageal, gastroesophageal, and gastric cancers are still among the leading causes of death worldwide. The introduction of immune checkpoint inhibitors (ICIs) has revolutionized the treatment strategy for several cancers. The combination of conventional chemotherapy with ICIs has been hypostatized to play a synergic effect over the chemotherapy alone regimen. Thus, the present systematic review and meta-analysis was conducted to compare the efficacy and safety of ICIs plus chemotherapy versus chemotherapy alone in patients suffering from advanced esophageal, gastroesophageal, and gastric cancers.PubMed, Scopus, Web of Science, and EMBASE databases together with the conference abstracts of ASCO and ESMO were searched systematically up to March 25, 2022. The studies were selected in two steps, title/abstract and full-text screening. The primary outcome was set at the efficacy of ICIs plus chemotherapy relative to the chemotherapy alone in terms of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). The secondary outcome was the safety in terms of treatment-related adverse events (TRAEs) and immune-related AEs.A total of 11 publications involving 6,732 patients were included. First-line ICIs plus chemotherapy showed superior effect over chemotherapy alone in terms of OS (hazard ratio [HR] 0.76, 95 %CI 0.72-0.81), PFS (HR 0.68, 95 %CI 0.61-0.75), ORR (risk ratio [RR] 1.29, 95 %CI 1.20-1.40), and DCR (RR 1.06, 95 %CI 1.03-1.09). Significant predictors of OS benefit in combination therapy versus chemotherapy alone were PDL-1 combined positive score (CPS) ≥ 10 compared to CPS < 10 (p = 0.012), tumor proportion score (TPS) ≥ 1 % compared to TPS < 1 % (p = 0.016), and male gender compared to the females (p = 0.024). In the safety analysis, ICIs plus chemotherapy showed a higher rate of TRAEs in terms of any grade AEs (RR 1.02, 95 %CI 1.00-1.04), grade ≥ 3 AEs (RR 1.16, 95 %CI 1.06-1.26), serious AEs (RR 1.63, 95 %CI 1.44-1.85), and AEs led to treatment discontinuation (RR 1.51, 95 %CI 1.37-1.67). Furthermore, the rate of immune-related AEs of any grade (RR 2.18, 95 %CI 1.55-3.05) and immune-related grade ≥ 3 AEs (RR 2.76, 95 %CI 1.85-4.13) were also higher in ICI combination therapy group relative to chemotherapy alone group.Our findings demonstrated that first-line ICIs plus chemotherapy versus chemotherapy alone prolonged OS and PFS in patients with advanced esophagogastric cancers. Also, the rate of AEs was remarkably higher in the combination group. As a result, identifying methods to prevent AEs without affecting the efficacy of ICIs is highly warranted.