Efficacy and safety of programmed cell death protein-1 inhibitor for first-line therapy of advanced gastric or gastroesophageal junction cancer: a network meta-analysis

Abstract

Background: This study conducted a network meta-analysis to evaluate and rank the safety and efficacy of programmed cell death protein-1 (PD-1) inhibitors for patients with advanced gastric or gastroesophageal junction cancer (GC/GEJC).

Methods: A systematic search was conducted in PubMed, Embase, and Cochrane Library databases to compare the efficacy and safety of different treatment regimens, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (TRAEs) in patients with advanced GC/GEJC.

Results: A total of six RCT studies were ultimately included in the analysis, involving 6,294 patients. Among them, 256 patients received PD-1 inhibitor monotherapy (pembrolizumab), 3,029 patients received a PD-1 inhibitor plus chemotherapy (1,047 with pembrolizumab, 1,154 with nivolumab, 327 with sintilimab, and 501 with tislelizumab), and 3,009 received either chemotherapy or chemotherapy plus placebo. Sintilimab plus chemotherapy had the highest SUCRA value for OS (85.2%), while nivolumab plus chemotherapy had the highest SUCRA values for both PFS and ORR (96.8% and 82.9%). Four PD-1 inhibitors plus chemotherapy significantly improved median OS and ORR compared with chemotherapy. Sintilimab plus chemotherapy, pembrolizumab plus chemotherapy, and nivolumab plus chemotherapy significantly improved median PFS compared with chemotherapy. For TRAEs of grade 3 or worse, pembrolizumab monotherapy had the highest SUCRA value. Tislelizumab plus chemotherapy, as well as sintilimab plus chemotherapy, did not increase the overall incidence of TRAEs and the incidence of grade 3 or worse TRAEs.

Conclusions: In the first-line treatment of advanced GC/GEJC, PD-1 inhibitors plus chemotherapy have been demonstrated to significantly improve OS, PFS, and ORR compared with chemotherapy. Among them, sintilimab plus chemotherapy achieved the highest SUCRA value for OS, and nivolumab plus chemotherapy achieved the highest SUCRA values for PFS and ORR. Regarding safety, tislelizumab plus chemotherapy and sintilimab plus chemotherapy did not increase the overall incidence of TRAEs and the incidence of grade 3 or worse TRAEs, with good tolerability and safety.

Keywords: PD-1 inhibitor; advanced gastric cancer; first-line treatment; gastroesophageal junction cancer; network meta-analysis.

Figure 1

Flowchart of study selection.

Figure 2

Network plots of direct comparisons for efficacy outcomes. Each node represents a treatment regimen. The size of each node is proportional to the number of patients included in the respective studies. The width of the connecting edges represents the number of RCTs.

Figure 3

Forest plot for overall survival (OS). (A), median OS; (B), 6-month OS; (C), 12-month OS; (D), 18-month OS; (E), 24-month OS.

Figure 4

Forest plot for PFS. (A), median PFS; (B), 6-month PFS; (C), 12-month PFS; (D), 18-month PFS.

Figure 5

ORR comparison. (A), network rankings of ORR by SUCRA; (B), forest plot for ORR.

Figure 6

Treatment-related adverse events (TRAEs) comparison. (A), network rankings of any-grade TRAEs by SUCRA; (B), forest plot for any-grade TRAEs; (C), network rankings of grade 3 or worse TRAEs by SUCRA; (D), forest plot for grade 3 or worse TRAEs. (E), network rankings of any-grade irAEs by SUCRA; (F), forest plot for any-grade irAEs.