The association of PD-L1 expression status and the PD-1/PD-L1 inhibitor-related toxicity profile in non-small cell lung cancer

Abstract

Objective: While PD-L1 expression serves as a predictive biomarker for programmed cell death 1 and its ligand (PD-1/PD-L1) inhibitor efficacy in patients with non-small cell lung cancer (NSCLC), its association with treatment-related adverse events (TRAEs) has yet to be fully elucidated. This study systematically evaluated the correlation between PD-L1 expression status and TRAEs in patients with NSCLC. Methods: We systematically searched the Cochrane Library, Embase, and PubMed databases from inception to June 30, 2024, to identify prospective clinical trials examining PD-1/PD-L1 inhibitors among NSCLC patients that reported treatment-related toxicity data stratified by PD-L1 expression. Results: Twenty-six prospective trials (N = 5,453) were analyzed. At the 1%, 25%, and 50% PD-L1 cutoffs, PD-L1-negative patients presented significantly reduced risks of grade 3–4 TRAEs (OR = 0.37, 0.53, 0.41; 95% CI = 0.18–0.77, 0.31–0.90, 0.19–0.97; P < 0.01, 0.02, 0.04). Similarly, PD-L1-negative patients had significantly reduced risks of AEs leading to treatment discontinuation at the 1% and 25% PD-L1 cutoffs (OR = 0.25, 0.38; 95% CI = 0.08–0.76, 0.16–0.89; P = 0.01, 0.03) but not at the 50% PD-L1 cutoff (OR 0.28, 95% CI 0.07–1.12, P = 0.07). Subgroup analyses revealed elevated all-grade TRAEs with the 22C3 immunohistochemistry assay (P < 0.001), whereas first-line therapy recipients (P = 0.006) and open-label trial participants (P = 0.002) presented increased grade 3–4 TRAEs. Conclusions: PD-L1 positivity may predict increased risks of grade 3–4 TRAEs and AEs leading to treatment discontinuation in NSCLC patients receiving PD-1/PD-L1 blockade. Furthermore, PD-L1 expression might be a useful biomarker for toxicity management in patients with NSCLC after PD-1/PD-L1 inhibitor treatment.