PD-1 inhibitors versus PD-L1 inhibitors in PD-L1–negative advanced non-small cell lung cancer: A meta-analysis of survival outcomes.

e20585 Background: Immune checkpoint inhibitors (ICIs) which target programmed cell death protein 1 receptor (PD-1) or its ligand (PD-L1) are used extensively in non-small cell lung cancer (NSCLC). In this study, we aimed to compare the relative efficacy of PD-1 inhibitors and PD-L1 inhibitors in PD-L1-negative advanced NSCLC. Methods: A systematic search was conducted in MEDLINE (via PubMed, Scopus, and Google Scholar) to identify randomized trials of advanced NSCLC that evaluated ICIs (anti-PD-1 or anti-PD-L1) and reported outcomes stratified by PD-L1 status, including data specific to PD-L1-negative patients. Hazard ratios (HRs) with 95% confidence intervals (CIs) and p-values for progression-free survival (PFS) and overall survival (OS) were extracted for the PD-L1-negative subgroup of each trial. Data were pooled using a random-effects meta-analysis, and comparisons between anti-PD-1 and anti-PD-L1 agents were performed. Subgroup analyses were conducted to explore variations in effect size. Results: The meta-analysis included 23 trials comprising 4,548 PD-L1-negative patients, representing 33% of all participants. PD-L1 testing was conducted in all studies. Anti-PD-1 agents significantly improved OS in PD-L1-negative patients with advanced NSCLC (HR 0.75, 95% CI 0.67–0.83, p < 0.01). In contrast, anti-PD-L1 agents did not show a statistically significant improvement in OS (HR 0.90, 95% CI 0.78–1.05, p = 0.18). Direct comparisons revealed that anti-PD-1 agents were associated with better OS compared to anti-PD-L1 agents (HR 0.83, 95% CI 0.67–0.99, p = 0.01). The benefit of anti-PD-1 agents was more pronounced in the first-line setting (pairwise HR 0.79, 95% CI 0.66–0.93, p = 0.01), whereas no significant difference was observed in later lines of therapy (pairwise HR 1.13, 95% CI 0.82–1.55, p = 0.45). These differences in OS were not reflected in PFS outcomes. Conclusions: Compared to checkpoint inhibitors targeting PD-L1, those targeting PD-1 are associated with better OS in PD-L1-negative advanced NSCLC, a finding influenced by trials performed in the first-line setting. This should be validated using real-world studies.