Immune-checkpoint inhibitors represent the new standard of care in patients with advanced NSCLC who progressed after first-line treatment. This work aim to assess any difference in both efficacy and safety profiles among Nivolumab, Pembrolizumab and Atezolizumab in pre-treated NSCLC patients. Randomized clinical trials comparing immune-checkpoint inhibitor versus docetaxel in pre-treated patients with advanced NSCLC were included and direct comparison meta-analysis of selected trials have been performed. Subsequently the summary estimates of Nivolumab, Pembrolizumab and Atezolizumab emerging from the direct meta-analysis were selected to provide the pooled estimates of hazard ratio (HR) and relative risk (RR) for the indirect comparisons among these agents. A total of 5 studies met the selection criteria and were included in the meta-analysis. Indirect comparisons for efficacy outcomes showed the RR for ORR nivolumab versus atezolizumab 1.66 (95% CI 1.07â2.58), pembrolizumab versus atezolizumab 1.94 (95% CI 1.30â2.90). No significant differences in both PFS and OS have been observed. Indirect comparisons for safety showed the RR for G3-5 AEs nivolumab versus pembrolizumab 0.41 (95% CI 0.29â0.60), nivolumab versus atezolizumab 0.50 (95% CI 0.35â0.72). No significant differences in both pneumonitis and discontinuation rate have been observed. The results of this work revealed that nivolumab and pembrolizumab are associated with a significant increase of ORR as compared to atezolizumab and nivolumab is associated with a significant lower incidence of G3-5 AEs as compared to the other drugs. These evidences could support the oncologists to select the best drug for each patient.