III期ADRIATIC研究中度伐利尤单抗在局限期小细胞肺癌患者中的群体药代动力学及暴露-反应分析。
完整摘要 · 中文译文
在ADRIATIC研究中，度伐利尤单抗单药作为局限期小细胞肺癌（LS-SCLC）的巩固治疗显示出良好的获益-风险特征。我们评估了度伐利尤单抗在LS-SCLC患者中的群体药代动力学（PopPK）和暴露-反应（E-R）关系。通过整合ADRIATIC研究的PK数据，更新了度伐利尤单抗的PopPK模型。个体暴露指标由经验贝叶斯估计得出，用于与安全性（不良事件[AE]）和疗效（无进展生存期[PFS]和总生存期[OS]）相关的E-R分析。具有时间依赖性清除率的二室模型充分描述了度伐利尤单抗的PK数据。基线清除率、中央室和外周室分布容积的典型参数估计值分别为0.273 L/天、3.49 L和2.35 L。所有已确定的协变量对度伐利尤单抗PK参数的影响被认为在临床上极小，其效应在典型值的80-125%范围内。按暴露四分位数分层的PFS或OS Kaplan Meier图提示，在选定剂量1500 mg下，度伐利尤单抗暴露与PFS或OS之间呈平台期关系。Cox PH模型分析未将暴露指标确定为OS或PFS风险的重要预后因素。在1500 mg IV Q4W剂量下，度伐利尤单抗PK暴露与安全性终点（包括3级及以上治疗相关AE、3级及以上特殊关注的治疗相关AE以及导致治疗中止的AE）之间观察到平坦的E-R关系。结果支持度伐利尤单抗单药的使用。 对于LS-SCLC患者，根据PopPK和E-R分析认为无需调整剂量。NCT03703297。
完整摘要 · 英文原文
Durvalumab monotherapy as a consolidation treatment for limited-stage small-cell lung cancer (LS-SCLC) demonstrated a favourable benefit-risk profile in the ADRIATIC study. We evaluated population pharmacokinetics (PopPK) and exposure-response (E-R) relationships of durvalumab in patients with LS-SCLC. The durvalumab PopPK model was updated by integrating PK data from the ADRIATIC study. Individual exposure metrics were derived from empirical Bayes estimates for E-R analyses relating to safety (adverse events [AEs]) and efficacy (progression-free survival [PFS] and overall survival [OS]). A two-compartment model with a time-dependent clearance adequately characterized durvalumab PK data. The typical parameter estimates for baseline clearance, central and peripheral volume of distribution were 0.273 L/day, 3.49 L and 2.35 L, respectively. All identified covariates are considered to have minimal clinical impact on durvalumab PK parameters with effect within 80-125% of typical values. Kaplan Meier plots of PFS or OS stratified by exposure quartiles suggested a plateaued relationship between durvalumab exposure and PFS or OS at the selected dose level of 1500 mg. The Cox PH model analysis did not identify exposure metrics as significant prognostic factors for the OS or PFS hazard. At 1500 mg IV Q4W, a flat E-R relationship was observed between durvalumab PK exposure and safety endpoints including Grade 3 + treatment-related AEs, Grade 3 + treatment-related AEs of special interest, and AEs leading to treatment discontinuation. The results support the use of durvalumab monotherapy for the patients with LS-SCLC, and no dose adjustment is considered necessary based on the PopPK and E-R analyses. NCT03703297.