Purpose:Pembrolizumab and tislelizumab have demonstrated significant clinical benefits in first-line treatment for advanced NSCLC. However, no head-to-head clinical trial has ever compared the optimal choice. Therefore, we conducted an indirect comparison to explore the optimal choice for advanced NSCLC combined with chemotherapy.Methods:We conducted a systematic review of randomized trials; the clinical outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). Indirect comparisons between tislelizumab and pembrolizumab were conducted with the Bucher method.Results:Data were abstracted from 6 randomized trials involving more than 2,000 participants. Direct meta-analysis showed that both treatment regimens improved clinical outcomes compared with chemotherapy alone (PFS: hazard ratio (HR)tis+chemo/chemo0.55, 95% CI 0.45–0.67; HRpem+chemo/chemo0.53, 95% CI 0.47–0.60; ORR: relative risk (RR)tis+chemo/chemo1.50, 95% CI 1.32–1.71; RRpem+chemo/chemo1.89, 95% CI 1.44–2.48). Regarding safety outcomes, tislelizumab and pembrolizumab have a higher risk in the incidence of grade 3 or higher AEs (RRtis+chemo/chemo1.12, 95% CI 1.03–1.21; RRpem+chemo/chemo1.13, 95% CI 1.03–1.24). The indirect comparison showed that there was no significant difference between tislelizumab plus chemotherapy and pembrolizumab plus chemotherapy in terms of PFS (HR: 1.04, 95% CI 0.82–1.31), ORR (RR: 0.79, 95% CI 0.59–1.07), the incidence of grade 3 or higher AEs (RR 0.99, 95% CI 0.87–1.12), and AEs leading to death (RR 0.70, 95% CI 0.23–2.09). In progression-free survival subgroup analysis, the results demonstrate no significant differences in PFS by PD-L1 TPS expression level, age, liver metastasis status, and smoking status between tislelizumab plus chemotherapy and pembrolizumab plus chemotherapy.Conclusion:The efficacy and safety of tislelizumab combination chemotherapy were not substantially different from pembrolizumab combination chemotherapy.