BACKGROUND: Immune checkpoint inhibitors (ICIs) are the preferred treatments for advanced non-small cell lung cancer (NSCLC) without targetable oncogene alterations. However, evidence in the elderly population (aged ≥ 65 years) remains limited. METHODS: We searched PubMed, Embase, Cochrane Library, Web of Science, and Scopus databases for eligible publications until September 30, 2024. The primary outcome of interest was overall survival (OS). A random-effects model was used for the statistical analysis. FINDINGS: A total of 35 phase 3 randomized controlled trials (RCTs) involving 9788 patients and 64 real-world studies involving 37,111 patients were included. Results from phase 3 RCTs revealed that ICIs significantly improved OS (hazard ratio [HR] = 0.78, 95% confidence interval [CI]: 0.74-0.82) and progression-free survival (PFS) (HR = 0.67, 95% CI: 0.60-0.75) compared to chemotherapy. The association between ICIs and improved OS was independent of patient characteristics (race and histological type) or treatment-related factors (ICI drug type, treatment mode, and treatment line). However, significantly prolonged OS was not observed in subgroups of aged ≥ 75 years and PD-L1 <
1%. In real-world studies, the pooled median OS of ICIs were 11.8 months (95% CI: 11.2-12.4)
Eastern Cooperative Oncology Group (EOCG) score, histological type, PD-L1 status, with immune-related adverse events (irAEs), and treatment mode were predictive for OS
rates of irAEs and discontinuation were numerically higher for combination therapy vs. monotherapy. INTERPRETATION: ICIs are associated with a significant improvement in OS and PFS compared to chemotherapy in elderly patients with advanced NSCLC. Nevertheless, some patient characteristics such as aged ≥ 75 years, ECOG score ≥ 2, and PD-L1 <
1% seem to have a negative impact on the efficacy of ICIs, while these findings require further validation in large RCTs. FUNDING: None.