Comparative safety of PD-1 and PD-L1 inhibitors in advanced solid tumors: a real-world cohort study with competing risk analysis.

backgroundReal-world evidence comparing long-term safety between PD-1 and PD-L1 inhibitors is limited, and the impact of competing mortality is unclear.

methodsThis retrospective cohort study utilized the TriNetX platform (2014-2024). Adults with advanced solid tumors initiating a PD-1 or PD-L1 inhibitor within 3 months of diagnosis were included. A 1:1 propensity score match created balanced cohorts. The primary outcome was the 1-year incidence of immune-related adverse events (irAEs). Standard Cox models and Fine-Gray competing risk models (accounting for death) were used to estimate hazard ratios (HRs) and subdistribution hazard ratios (sHRs), respectively.

resultsAfter matching, 22,672 patients (11,336 per group) were analyzed. In standard Cox analysis, PD-L1 inhibitors were associated with a lower risk of skin rash (HR 0.66, 95% CI 0.56-0.78), colitis (HR 0.79, 0.71-0.87), and nephritis (HR 0.71, 0.54-0.94) compared to PD-1 inhibitors. The competing risk analysis revealed that all-cause mortality was the overwhelmingly dominant outcome. Consequently, PD-L1 inhibitor use was associated with uniformly lower sHRs for every irAE analyzed (range: 0.85-0.88), with the sHR for mortality itself at 0.88 (0.84-0.92). This pattern, indicating the safety signal was heavily confounded by survival, was consistent across sex and age subgroups but more pronounced in males and older patients.

conclusionPD-L1 inhibitors are associated with a lower risk of specific irAEs. However, mortality is the dominant competing risk in advanced cancer, fundamentally shaping safety assessments. Real-world studies must account for competing mortality to avoid distorted conclusions.