Risk of Neurological Adverse Events Between PD-L1 and PD-1 Inhibitors in South Korean Patients with Lung Cancer: A Target Trial Emulation Framework

BACKGROUND AND OBJECTIVE: Differences in programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) inhibitors may influence their impacts on immune responses and result in distinct patterns of neurological adverse events (NAEs), which are uncommon but clinically significant. Therefore, we aimed to compare the risk of NAEs between PD-1 and PD-L1 inhibitors. METHODS: We conducted a retrospective cohort study using a target trial emulation framework with nationwide data of patients with newly diagnosed lung cancer. Propensity score matching was used to minimize baseline differences. A multivariate competing risk hazard model was used to assess NAE incidence. Kaplan-Meier curves and Mann-Whitney U were used to depict cumulative incidence and evaluate time to onset, respectively. RESULTS: Among the 931 patients per group, peripheral NAEs were more frequent with PD-L1 inhibitors (19.2% vs 14.1%), with a higher incidence density (23.91 vs 17.04 cases per 100 person-years). Within 30 days, NAEs were approximately three times more common with PD-1 inhibitors; however, beyond 360 days, the risk was higher with PD-L1 inhibitors (hazard ratio 1.83, p < 0.05). NAEs were more frequent with PD-L1 inhibitors in patients who had received prior chemotherapy (p < 0.05) and metastasis (p < 0.05). The median time to onset was similar between the two groups (141 vs 138 days, p = 0.69). CONCLUSIONS: To our knowledge, this study is one of the first studies to directly compare NAE risk between PD-L1 and PD-1 inhibitors using real-world data from South Korean patients with lung cancer. Given the expanding global use of immune checkpoint inhibitors, it offers valuable evidence for guiding future treatment strategies.