Fixed-Dose Serplulimab Strategy Supported by Comprehensive Pharmacokinetic Analysis

A comprehensive investigation has validated the pharmacokinetic (PK), exposure-response (E-R), and safety profile of serplulimab, a fully humanized IgG4 anti-PD-1 monoclonal antibody, in patients with extensive-stage small-cell lung cancer (ES-SCLC).¹ The analysis, published in Clinical and Translational Science, demonstrated that the currently approved regimen achieves pharmacodynamic saturation without incremental benefit from higher exposures, supporting its current clinical use.

Serplulimab received Chinese regulatory approval in 2022 and European Medicines Agency (EMA) authorization in February 2025, based on the pivotal phase III ASTRUM-005 trial, which demonstrated a median overall survival (OS) of 15.4 months versus 10.9 months with placebo plus chemotherapy (HR, 0.63).² That study established serplulimab as the PD-1 inhibitor yielding the greatest OS benefit to date in first-line ES-SCLC. The present analysis evaluated whether population-specific covariates necessitate dose adjustments and explored the relationship between exposure and clinical outcomes, drawing on data from 1,144 subjects enrolled across 8 Phase I-III trials, including ASTRUM-005.¹

The population pharmacokinetic (PopPK) model characterized serplulimab with a linear two-compartment framework incorporating time-dependent clearance that accurately described its pharmacologic behavior across trials. Simulations estimated a time-to-half-maximal clearance change (T₅₀) of 106 days, corresponding to median half-lives of 19 days after the first dose and 24.4 days at steady state. This is somewhat longer than values reported for pembrolizumab and nivolumab, suggesting durable systemic exposure and consistent PD-1 receptor engagement throughout therapy. Immunogenicity was minimal, with antidrug antibodies (ADA) detected in only 2.01% of patients; a 13.3% increase in clearance among ADA-positive subjects was not clinically meaningful.

Covariate analysis showed that age, BMI, hepatic enzymes, renal function, and ECOG performance status had no significant effect on PK parameters. Among statistically significant factors, body weight, serum albumin, and sex were identified but remained within the accepted bioequivalence range (0.8-1.25). A higher body weight was associated with modestly lower exposure (ratios 0.88-1.14), whereas higher albumin correlated with slightly greater exposure (ratios 0.818-1.17). “These findings support the conclusion that no dose adjustments for serplulimab are necessary based on these covariates,” the investigators concluded.

Efficacy analyses from 389 patients with SCLC from ASTRUM-005, with exposure-response analyses, demonstrated a flat relationship between serplulimab exposure and clinical outcomes. No significant difference in progression-free survival (PFS) was identified, and while a numerical trend toward longer OS appeared in higher-exposure groups, this association was eliminated after multivariate adjustment for baseline prognostic factors (P > .05). However, established prognostic indicators such as baseline lactate dehydrogenase (LDH) and tumor burden were identified as independent predictors of OS (P < .05 for both), whereas serplulimab exposure itself had no significant effect (P > .05).

Safety analyses mirrored these efficacy findings, revealing no monotonic relationship between maximum concentration (C_max1) or average concentration (C_avg1) and adverse-event probability. Rates of adverse effects, including grade ≥ 3 treatment-emergent AEs (69.1%), grade ≥ 3 adverse drug reactions (29.6%), serious AEs (36.7%), and immune-related AEs (32.5%), remained stable across exposure quartiles. These findings align with the ASTRUM-005 results, where grade ≥ 3 TEAEs occurred in 82.5% of the serplulimab arm versus 80.1% with placebo, and immune-related AEs in 37.0% versus 18.4%, respectively.²

The results from this study confirm the current 4.5 mg/kg Q3W regimen as optimal, requiring no dose modifications based on demographic or clinical characteristics.¹ As the authors note, the absence of an exposure-dependent response reflects “pharmacodynamic saturation typical of PD-1 blockade,” and increasing the dose “would not overcome unfavorable prognostic biomarkers or lead to improved clinical outcomes.”

Baseline LDH and tumor burden, not drug exposure, remain the dominant predictors of survival in ES-SCLC. Given the short observation periods in the study, researchers note that they “anticipate that the inclusion of longer-term follow-up data in future analyses will further refine the precision of this parameter estimation.”

References

1. Wang K, Shen Y, Hu C, et al. Population pharmacokinetics and exposure-response analysis of serplulimab in small cell lung cancer patients. Clin Transl Sci. 2025;18(9):e70322. doi:10.1111/cts.70322

2. Cheng Y, Han L, Wu L, et al. Effect of first-line serplulimab vs placebo added to chemotherapy on survival in patients with extensive-stage small cell lung cancer: The ASTRUM-005 randomized clinical trial. JAMA. 2022;328(12):1223-1232. doi:10.1001/jama.2022.16464