Efficacy and safety in triple-versus dual therapy regimens for driver gene-negative nonsquamous non-small cell lung cancer: a systematic review and network meta-analysis

Abstract Background Due to the absence of targetable molecular targets, the treatment of driver gene-negative nonsquamous non-small cell lung cancer (NSCLC) relies primarily on antiangiogenic agents combined with chemotherapy (Antiangio-Ab + Chemo) or immune checkpoint inhibitors combined with chemotherapy regimens (ICI + Chemo). Furthermore, triple therapy strategies combining immunotherapy, antiangiogenic therapy and chemotherapy (ICI + Antiangio-Ab + Chemo) are increasingly utilized in clinical management of driver gene-negative nonsquamous NSCLC patients. However, evidence comparing the relative benefits of triple therapy versus dual therapy remains limited. This study employs a network meta-analysis to systematically evaluate the efficacy and safety of triple versus dual regimens in this patient population to provide more actionable guidance for clinical practice. Objective This study aims to compare the relative efficacy and safety of triple combination therapy against dual combination therapies of (ICI + Chemo versus Antiangio-Ab + Chemo) through network meta-analysis. Methods A systematic search was conducted across the PubMed, EMBASE, Cochrane, and Web of Science databases from inception to 6 January 2026. Studies comparing triple therapy (ICI + Antiangio-Ab + Chemo) with dual therapy (ICI + Chemo or Antiangio-Ab + Chemo) in driver gene-negative nonsquamous non-small cell lung cancer patients were included. The primary endpoints included progression-free survival (PFS) and overall survival (OS). Secondary endpoints included the overall response rate (ORR) and Grade ≥ 3 Treatment-Related Adverse Events (TRAEs). Statistical analysis was conducted using R software. Results Five eligible studies involving 2452 patients were included. Regarding PFS, ICI + Antiangio-Ab + Chemo demonstrated significantly superior efficacy compared to Antiangio-Ab + Chemo (HR, 0.63; 95% CI 0.5–0.86). It also showed improved efficacy compared with ICI + Chemo, although the difference was not significant (HR, 0.81; 95% CI 0.63–1.1). In the PFS subgroup analysis, no statistically significant differences were observed between the low PD-L1 expression subgroup and the moderate PD-L1 expression subgroup. In the high-expression cohort (PD-L1 ≥ 50%), we observed that the triple-agent regimen was significantly more effective than Antiangio-Ab + Chemo (HR, 0.44; 95% CI 0.21–0.94). In terms of OS, compared with Antiangio-Ab + Chemo, the dual therapy of ICI + Chemo had significantly better efficacy (HR, 0.77; 95% CI 0.61–0.98). Compared with Antiangio-Ab + Chemo, the triple combination of ICI + Antiangio-Ab + Chemo also showed an advantage, and the difference was statistically significant (HR, 0.81; 95% CI 0.67–0.99). No significant differences were noted in the safety profiles. Conclusion These findings suggest that the ICI + Antiangio-Ab + Chemo triple regimen may offer potential benefits for patients with driver gene-negative nonsquamous NSCLC. For PFS, the triple regimen was superior to Antiangio-Ab + Chemo overall, with a statistically significant difference in the high PD-L1 subgroup but not in low/moderate subgroups; it also showed a non-significant advantage over ICI + Chemo. For OS, both ICI + Antiangio-Ab + Chemo and ICI + Chemo demonstrated statistically significant superiority over Antiangio-Ab + Chemo, whereas the comparison between the two ICI-containing regimens was not significant.