Abstract
While PD-L1 antibodies have demonstrated efficacy in small cell lung cancer, the therapeutic benefits remain limited. To address this unmet medical need, serplulimab was developed as an innovative monoclonal antibody targeting PD-1. This study evaluated the pharmacokinetic (PK) properties of serplulimab and their relationship with efficacy and safety in patients with extensive-stage small cell lung cancer (ES-SCLC), using population pharmacokinetics (PopPK) and exposure-response (E-R) analysis to inform dose selection. Data from 1144 patients across eight Phase I-III clinical trials supported a two-compartment PopPK model with time-dependent clearance. Cox proportional hazards models were employed to analyze the correlation between exposure (C(avg1) and C(min1)) and overall survival (OS)/progression-free survival (PFS), and adverse events (AEs) with exposure (C(avg1) and C(max1)). Body weight, albumin (ALB), and gender significantly influenced the clearance and volume distribution of serplulimab; however, the observed differences in exposure ratio did not reach clinically relevant thresholds (0.8-1.25), thereby obviating the need for dose adjustments. Safety analysis revealed no monotonic increase in AE probability with increasing exposure (p > 0.05). Efficacy analysis indicated no significant correlation between exposure and OS (p > 0.05), whereas lactate dehydrogenase (LDH) and tumor burden emerged as significant predictors of OS (p < 0.05). Results confirm favorable PK and safety of serplulimab at the recommended dose, requiring no adjustment for above covariates. These findings suggest that the current dose is on the plateau of the E-R curve, and dose escalation is unlikely to improve clinical outcomes. Trial Registration: ClinicalTrials.gov identifier: NCT03952403, NCT04818359, NCT05246164, NCT04747236, NCT03973112, NCT04297995, NCT04778904, NCT04063163.