BACKGROUND: To explore the safety of PD-L1 inhibitors vs. PD-1 inhibitors in extensive-stage small-cell lung cancer (ES-SCLC) and non-small-cell lung cancer (NSCLC). RESEARCH DESIGN AND METHODS: PubMed, EMBASE, and the Cochrane Library were searched up to 20 December 2023. Randomized controlled trials on patients with NSCLC/ES-SCLC treated with PD-1/PD-L1 inhibitor were included and synthesized with Bayesian network meta-analysis. RESULTS: This meta-analysis included 58 studies. Regarding grade ≥ 3 treatment-related adverse events (TRAEs), PD-L1 inhibitors had better safety compared with PD-1 inhibitors when combined with chemotherapy in resectable NSCLC, presenting larger surface under the cumulative ranking (SUCRA) (0.577 vs. 0.168), similar with those in advanced NSCLC and ES-SCLC. The safety of PD-L1 inhibitors were better than PD-1 inhibitors regarding grade ≥ 3 pneumonia in resectable NSCLC when combined with chemotherapy (0.648 vs. 0.307), as well as in advanced NSCLC and ES-SCLC. When combined with chemotherapy, PD-L1 inhibitors had better safety regarding grade ≥ 3 pneumonitis, compared to PD-1 inhibitor (resectable NSCLC: 0.934 vs. 0.019
advanced NSCLC: 0.618 vs. 0.584
ES-SCLC: 0.505 vs 0.059). CONCLUSION: PD-L1 inhibitors might be a safer option than PD-1 inhibitors regarding grade ≥ 3 TRAEs and pneumonia, monotherapy or combined with chemotherapy, and when combined with chemotherapy regarding grade ≥ 3 pneumonitis. REGISTRATION: PROSPERO (CRD42024620372).