Effectiveness and safety of PD-1/PD-L1 or CTLA4 inhibitors combined with chemotherapy as a first-line treatment for lung cancer: A meta-analysis

Background: Immune checkpoint inhibitors (ICIs) combined with chemotherapy have been applied as a first-line treatment for lung cancer, but consistent beneficial results have not been documented. Therefore, our meta-analysis aimed to evaluate the effectiveness and safety of combination therapy to promote its application. Methods: We searched electronic databases for studies that estimated the safety and efficacy of combined therapy. The objective response rate (ORR) and disease control response (DCR) parameters were evaluated with odds ratio (OR) values of the combination arm over the non-combination arm. Hazard ratios (HR) and its 95% confidence intervals (95% CI) were used to calculate progression-free survival (PFS) and overall survival (OS) in the combination and non-combination arms. All treatment-related adverse events (TRAEs) and 3 to 5 TRAEs were expressed as relative risk (RR) values of the combination arm over the noncombination arm. Results: Ten eligible studies involving 4,887 patients were identified. The pooled ORs for ORR and DCR were 1.85 (95% CI: 1.30-2.63, P<0.01) and 1.14 (95% CI: 0.70-1.86, P<0.01), respectively. The pooled HRs for PFS and OS were 0.67 (95% CI: 0.58-0.79, P<0.001) and 0.76 (95% CI: 0.65-0.88, P<0.001), respectively. in subgroup analysis, ORR and DCR were significantly improved in the programmed cell death-I/LI (PD-1/L1) blockade for non-small cell lung cancer (NSCLC) group (subgroup A), with a combined OR values of 2.36 (95% CI: 1.79-3.13, P<0.001) and 1.92 (95% CI: 1.10-3.35, P<0.001), respectively. However, no significant benefits were observed in the cytotoxic T lymphocyte antigen-4 (CTLA-4) blockade for small cell lung cancer (SCLC) (subgroup B) and CTLA-4 blockade for NSCLC groups (subgroup C). In addition, a significant improvement in PFS was observed in subgroup A, subgroup B and subgroup C, with pooled HR values of 0.58 (95% CI: 0.52-0.63, P<0.001), 0.86 (95% Cl: 0.76-0.97, P<0.05) and 0.83 (95% CI: 0.68-1.00, P<0.05), respectively. Only subgroup A exhibited an OS benefit, with a combined HR value of 0.67 (95% CI: 0.55-0.81, P<0.001). Moreover, as the expression of PD-L1 increased, the PFS and OS benefits were more significantly. Furthermore, patients without central nervous system (CNS) metastasis who were treated with PD-1/L1 inhibitors had a longer OS than patients with CNS metastasis (HR: 0.67, 95% CI: 0.55-0.80, P<0.001). Finally, combined therapy was associated with 3 to 5 TRAEs (RR: 1.26, 95% CI: 1.08-1.47; P<0.01). Conclusions: Patients treated with immunotherapy and chemotherapy in combination exhibited superior in ORR, DCR, PES and Os as well as slightly increased - RAE levels compared with those of patients treated with either monotherapy.