The benefits and risks of CTLA4 inhibitor plus PD1/PDL1 inhibitor in stage IIIB/IV non‐small cell lung cancer: A systematic analysis and meta‐analysis based on randomized controlled trials

WHAT IS KNOWN AND OBJECTIVE: Although immune checkpoint inhibitors (ICIs) have shown clinical benefit for patients with non-small cell lung cancer (NSCLC), the efficacy of the combination of ICIs targeting different pathways is still unclear. We performed this meta-analysis to explore the efficacy of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor plus programmed cell death 1 receptor (PD-1)/programmed cell death receptor ligand 1 (PD-L1) inhibitor therapy (CP) for NSCLC IIIB/IV patients. METHODS: We systematically searched the main databases for relevant studies. The main outcomes were overall survival (OS) and progression-free survival (PFS). RESULTS AND DISCUSSION: We identified 3526 articles, including 5 randomized controlled trials (RCTs) (4377 patients), in our meta-analysis. We conducted two comparisons of CP versus chemotherapy or PD1/PDL1 inhibitor (P). Compared with chemotherapy, CP was more effective, with better OS (hazard ratio [HR]: 0.77, 95% CI [confidence interval]: 0.66-0.91; p = 0.001), better PFS (HR: 0.77, 95% CI: 0.70-0.85; p < 0.00001) and comparable objective response rate (ORR) (risk ratio [RR]: 1.27, 95% CI: 0.98-1.65; p = 0.07); in terms of toxicity, CP was comparable to chemotherapy across all-grade adverse events (AEs) (RR: 0.87, 95% CI: 0.73-1.03; p = 0.11) and grade 3-5 AEs (RR: 0.85, 95% CI: 0.63-1.14; p = 0.27). Compared with P, CP had no superiority in efficacy in terms of the OS (HR: 1.04, 95%CI: 0.86-1.24; p=0.70), PFS (HR: 0.95, 95%CI: 0.75-1.22; p = 0.70) and the ORR (RR: 1.07, 95% CI: 0.95-1.21; p = 0.27) but CP was more effective than P when PD-L1 expression was <1% (RR: 0.77,95%CI: 0.60-0.98; p = 0.04); in terms of toxicity, CP was associated with increased all-grade AEs (RR:1.07, 95% CI: 0.97-1.19; p = 0.18) and grade 3-5 AEs (RR:1.58, 95% CI: 1.21-2.07; p = 0.0008). WHAT IS NEW AND CONCLUSION: CP is a beneficial therapeutic schedule with longer PFS and OS than chemotherapy and has an acceptable, manageable grade 3-4 AE rate in IIIB/IV NSCLC. However, compared with P, CP results in better OS only in patients with PD-L1 expression <1%.