AbbVie Deutschland GmbH Co. KG, Clinical Pharmacology and Pharmacometrics Ludwigshafen, Ludwigshafen, Germany.
AbbVie Inc., Clinical Pharmacology and Pharmacometrics, North Chicago, Illinois, USA.
J Clin Pharmacol. 2022 Oct;62(10):1236-1246. doi: 10.1002/jcph.2061. Epub 2022 May 5.
BRCA-Mutated Advanced Breast Cancer (BROCADE3) is a phase 3 study, evaluating veliparib in combination with carboplatin/paclitaxel with continuation as monotherapy if carboplatin/paclitaxel is discontinued in patients with germline BRCA1/2 mutation-associated, advanced human epidermal growth factor receptor 2-negative breast cancer. The objective of the current analysis was to characterize the veliparib exposure-response relationships for efficacy (progression-free survival [PFS]) and safety in this study. Exposure-efficacy analyses of PFS were conducted using Kaplan-Meier plots and cox proportional hazards (CPH) models using treatment alone or both treatment and exposure as time-dependent predictors to estimate the effect of veliparib in combination with carboplatin/paclitaxel and as monotherapy. The cox proportional hazards model with only treatment as the time-varying predictor estimated a statistically significant benefit of veliparib monotherapy compared to placebo monotherapy (hazard ratio, 0.49; 95%CI, 0.33-0.73) and a modest, non-statistically significant benefit (hazard ratio, 0.81; 95%CI, 0.62-1.05) of adding veliparib to carboplatin/paclitaxel. Inclusion of exposure as an additional time-varying predictor in the cox proportional hazards model indicated a flat exposure-response relationship between the veliparib exposure and PFS when veliparib was administered in combination with carboplatin/paclitaxel or as monotherapy. The exposure-safety analysis did not reveal any meaningful exposure-dependent trend in the incidence of adverse events of interest. These analyses support the dose regimen of veliparib (120 mg twice daily) in combination with carboplatin/paclitaxel and continuation of veliparib (300-400 mg twice daily) as monotherapy if carboplatin/paclitaxel were discontinued before disease progression in this patient population. This study is registered with ClinicalTrials.gov with a registration ID: NCT02163694.
BRCA 突变型晚期乳腺癌（BROCADE3）是一项 3 期研究，评估维利帕利联合卡铂/紫杉醇，在存在胚系 BRCA1/2 突变相关的、晚期人表皮生长因子受体 2 阴性乳腺癌患者中，如果卡铂/紫杉醇停药，则继续维利帕利单药治疗。本分析的目的是描述该研究中维利帕利的暴露-反应关系对疗效（无进展生存期[PFS]）和安全性的影响。使用 Kaplan-Meier 图和 Cox 比例风险（CPH）模型进行 PFS 的暴露-疗效分析，分别使用治疗单独或同时作为时间依赖性预测因素，以估计维利帕利联合卡铂/紫杉醇和单药治疗的效果。仅将治疗作为时变预测因素的 Cox 比例风险模型估计维利帕利单药治疗与安慰剂单药治疗相比具有统计学显著获益（风险比，0.49；95%CI，0.33-0.73），且添加维利帕利至卡铂/紫杉醇的获益适度且无统计学意义（风险比，0.81；95%CI，0.62-1.05）。将暴露作为 Cox 比例风险模型中的附加时变预测因素纳入后，表明当维利帕利联合卡铂/紫杉醇或单药治疗时，维利帕利的暴露与 PFS 之间呈平坦的暴露-反应关系。暴露-安全性分析未发现任何有意义的与暴露相关的不良事件发生率的趋势。这些分析支持维利帕利（120 mg 每日两次）联合卡铂/紫杉醇的剂量方案，以及如果卡铂/紫杉醇在疾病进展前停药，则继续维利帕利（300-400 mg 每日两次）单药治疗的方案。本研究在 ClinicalTrials.gov 注册，注册号为 NCT02163694。
