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Introduction: The addition of programmed cell death protein-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitors to first-line chemotherapy (CT) improved the outcomes of advanced NSCLC. Nonetheless, no direct comparison exists between these combination treatments. Methods: We performed a meta-analysis of randomized clinical trials to evaluate and compare the efficacy and safety of PD-(L)1 inhibitors in combination with first-line CT for advanced NSCLC. Results: A total of eight randomized clinical trials were included. The addition of a PD-(L)1 inhibitor to CT improved progression-free survival, overall survival, and objective response rate compared with CT alone. The risk of grade greater than or equal to 3 treatment-related adverse events was slightly higher with the addition of a PD-(L)1 inhibitor to CT as compared with CT alone. A subgroup analysis according to the targeted receptor (PD-1 versus PD-L1) revealed that the addition of a PD-1 inhibitor to CT led to better objective response rate (p = 0.0001), progression-free survival (p = 0.006), and overall survival (p = 0.002) compared with that of a PD-L1 inhibitor. The risk of grade greater than or equal to 3 treatment-related adverse events was significantly increased with the addition of a PD-L1 inhibitor to CT, but not with the addition of a PD-1 inhibitor. A direct comparison using the meta-regression analysis confirmed the statistical significance of all previous findings. Conclusions: On the basis of this meta-analysis, the addition of a PD-1 inhibitor to first-line CT revealed statistically significant better outcomes and less additional toxicity compared with that of a PD-L1 inhibitor, as compared with CT alone, in advanced NSCLC, regardless of PD-L1 status.