Efficacy and safety of immune checkpoint inhibitors in advanced gastric or gastroesophageal junction cancer: a systematic review and meta-analysis

Abstract

Background: Immune checkpoint inhibitors (ICI) have shown promising prospects in gastroesophageal junction (G/GEJ) cancer immunotherapy, many clinical trials have been carried out. Objective: To evaluate the efficacy and safety of ICI in G/GEJ cancer. Methods: The published English articles of PubMed, Cochrane Library, Embase, Web of Science were searched up to 30/09/2018. The efficacy and safety of ICI were analyzed by meta-analysis. Results: A total of 2003 patients from nine clinical trials were included. Anti-PD-1 treatment improved the 12-month, 18-month overall survival (OS) rate (RR, 1.79 p = 0.013; 2.20 p = 0.011) and prolonged the duration of response (DOR) (MSR, 3.27 p < 0.001). The objective response rate (ORR) in PD-L1+ patients was greater than PD-L1- (RR, 4.31 p < 0.001). Microsatellite instability-high (MSI-H) patients had higher ORR and disease control rate (DCR) than microsatellite stability (MSS) (RR, 3.40 p< 0.001; 2.26 p= 0.001). The most common grade ≥3 treatment-related adverse events (TRAEs) were fatigue, aspartate aminotransferase increased, hepatitis, pneumonitis, colitis, hypopituitarism. The TRAE incidence of anti-PD-1/PD-L1 was less than chemotherapy (TRAE RR = 0.64 p< 0.001; ≥3 TRAE RR = 0.37 p < 0.001). The incidence of ≥3 TRAEs of anti-PD-1/PD-L1 treatment was less than that of anti-CTLA-4 (11.7% vs 43.9%). Conclusions: ICI treatment could improve some but not all survival endpoints to advanced or metastatic G/GEJ cancer patients suggesting modest benefit and less adverse reactions. Anti-PD-1/PD-L1 therapy was more effective to PD-L1+, MSI-H, EBV+, or high tumor mutational burden patients.

Keywords: CTLA-4; Immune checkpoint inhibitor; PD-1; PD-L1; gastric or gastroesophageal junction cancer; meta-analysis.

Figure 1.

(a) Flow diagram of study retrieval and selection. (b) Risk of bias summary of randomized controlled trials. + low risk, ? unclear risk, − high risk.

Figure 2.

(a) Forest plots of different subgroups. (a) ORR and DCR. (b) PFS time, OS time and DOR. CI, confidence interval; CTLA-4, cytotoxic T lymphocyte antigen 4; DCR, disease control rate; DOR, duration of response; ICI, immune checkpoint inhibitor; MSR, median survival ratio; ORR, objective response rate; OS, overall survival; PD-1, programmed death-1; PD-L1, programmed death ligand 1; PFS, progression-free survival; RR, relative risk.

Figure 3.

(a) Forest plots of PFS and OS rates of different subgroups. (b) Forest plots of HR of PFS and OS of anti-PD-1/PD-L1 treatment. CI, confidence interval; CTLA-4, cytotoxic T lymphocyte antigen 4; HR, hazard ratio; ICI, immune checkpoint inhibitor; OS, overall survival; PD-1, programmed death-1; PD-L1, programmed death ligand 1; PFS, progression-free survival; RR, relative risk.

Figure 4.

Forest plots of PD-L1+ patients. (a) ORR and DCR. (b) PFS time, OS time and DOR. (c) HR of OS. CI, confidence interval; DCR, disease control rate; HR, hazard ratio; MSR, median survival ratio; ORR, objective response rate; OS, overall survival; PD-1, programmed death-1; PD-L1, programmed death ligand 1; PFS, progression-free survival; RR, relative risk; vs versus

Figure 5.

(a) Forest plots of ORR and DCR of MSI-H patients. (b) Forest plots of TRAE and ≥3 TRAE of anti-PD-1/PD-L1 treatment vs chemotherapy. CI, confidence interval; DCR, disease control rate; MSI-H, microsatellite instability-high; MSS, microsatellite stability; ORR, objective response rate; PD-1, programmed death-1; PD-L1, programmed death ligand 1; RR, relative risk; TRAE, treatment-related adverse event; vs versus.

Figure 6.

Forest plots of HR of OS in different geographical regions, anatomical location, histological types, and ECOG scores. CI, confidence interval; ECOG, Eastern Cooperative Oncology Group, HR, hazard ratio; GC, gastric cancer; GEJC, gastroesophageal junction cancer; OS, overall survival.