Population Pharmacokinetics and Exposure–Response Analysis of Tremelimumab 300 mg Single Dose Combined with Durvalumab 1500 mg Q4W (STRIDE) in Patients with Unresectable Hepatocellular Carcinoma

银耳霉素 杜瓦卢马布 医学 人口 肿瘤科 内科学 药代动力学 肝细胞癌 癌症 环境卫生 免疫疗法 无容量 易普利姆玛
作者
KyoungSoo Lim,Aburough Abegesah,Chunling Fan,Zhijian He,Xuyang Song,Cecil Chen,Alejandra Negro,M. Makowsky,Charu Gupta,Song Ren,Alex Phipps,Megan Gibbs,Diansong Zhou
出处
期刊:The Journal of Clinical Pharmacology [Wiley]
卷期号:63 (11): 1221-1231 被引量:1
标识
DOI:10.1002/jcph.2288
摘要

A novel single-dose regimen of 300 mg tremelimumab in combination with durvalumab (STRIDE) has demonstrated a favorable benefit-risk profile in the phase 1/2 Study 22 trial (in patients with unresectable hepatocellular carcinoma, uHCC) and in the phase 3 HIMALAYA study. The current analysis evaluated the population pharmacokinetics (PopPK) of tremelimumab and durvalumab, and the exposure-response (ER) relationship for efficacy and safety of STRIDE in patients with uHCC. Previous PopPK models for tremelimumab and durvalumab were updated using data from previous studies in various cancers combined with data from Study 22 and HIMALAYA. Typical population mean parameters and associated inter- and intra-individual variability were assessed, as was the influence of covariates. Individual exposure metrics were derived from the individual empirical Bayes estimates as drivers for ER analysis related to efficacy and safety from HIMALAYA. The observed pharmacokinetics of tremelimumab in uHCC were well described by a 2-compartment model with both linear and time-dependent clearance. All identified covariates changed tremelimumab PK parameters by <25%, and thus had minimal clinical relevance; similar results were obtained from durvalumab PopPK analysis. None of tremelimumab or durvalumab exposure metrics were significantly associated with overall survival (OS), progression-free survival (PFS), or adverse events. Baseline aspartate aminotransferase and neutrophil-to-lymphocyte ratio (NLR) were associated with OS (P < .001) by the Cox proportional hazards model. No covariate was identified as a significant factor for PFS. No dose adjustment for tremelimumab or durvalumab is needed based on PopPK covariate analyses or ER analyses. Our findings support the novel STRIDE dosing regimen in patients with uHCC.
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