西妥昔单抗每两周给药一次与标准每周给药一次在转移性结直肠癌中的临床非劣效性的模型信息证据

IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Clinical Pharmacology & Therapeutics Pub Date : 2024-08-12 DOI:10.1002/cpt.3345
Ana-Marija Milenković-Grišić, Siobhán Hayes, Colm Farrell, Yoshihiro Kuroki, Mauro Bertolino, Karthik Venkatakrishnan, Pascal Girard
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引用次数: 0

摘要

西妥昔单抗最初被开发并批准作为不可切除转移性结直肠癌(mCRC)患者的一线治疗药物,每周给药(250 毫克/平方米 Q1W,400 毫克/平方米负荷剂量)。最近,一些卫生机构批准了每两周一次的用药计划(500 毫克/平方米 Q2W)。Q2W与化疗同步进行,应能提高患者的便利性和医疗资源的利用率。在此,我们通过药物计量学建模和临床试验模拟(CTS),证明西妥昔单抗 Q2W 给药与 Q1W 给药相比无劣效性。我们使用与总生存期(OS)相关的群体暴露-肿瘤大小(TS)模型,对来自五项 I-III 期临床试验的 852 名 KRAS 野生型 mCRC 患者接受 Q1W 或 Q2W 西妥昔单抗治疗的汇总数据进行了建模;暴露量来自之前建立的群体药代动力学模型。半机制 TS 模型改编自 Claret 模型,纳入了与西妥昔单抗 2 周内浓度-时间曲线下面积(AUC)成比例的杀伤率,并将东部合作肿瘤学组(ECOG)状态作为基线 TS 的协变量。OS 采用 Weibull 危险模型,以 ECOG、基线 TS、原发肿瘤位置和 8 周时 TS 的预测变化百分比作为协变量。基于模型的模拟显示,Q2W 与 Q1W 西妥昔单抗的早期肿瘤缩小率和生存率无差别。CTS 在 1,000 项试验中评估了 OS 非劣效性(预定义差为 1.25),每项试验有 2,000 名虚拟患者接受 Q2W 或 Q1W 西妥昔单抗治疗(1:1),结果显示 94% 的病例具有非劣效性。综上所述,这些分析为 Q2W 与 Q1W 西妥昔单抗在 mCRC 中的临床非劣效性提供了基于模型的证据,并为患者和医疗服务提供者带来了潜在的益处。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Model-informed Evidence for Clinical Non-inferiority of Every-2-Weeks Versus Standard Weekly Dosing Schedule of Cetuximab in Metastatic Colorectal Cancer

Cetuximab was initially developed and approved as a first-line treatment in patients with unresectable metastatic colorectal cancer (mCRC) for weekly administration (250 mg/m2 Q1W with 400 mg/m2 loading dose). An every-2-weeks schedule (500 mg/m2 Q2W) was approved recently by several health authorities. Being synchronized with chemotherapy, Q2W administration should improve patients' convenience and healthcare resource utilization. Herein, we present evidence of non-inferiority of Q2W cetuximab, compared with Q1W dosing using pharmacometrics modeling and clinical trial simulation (CTS). Pooled data from five phase I–III clinical trials in 852 patients with KRAS wild-type mCRC treated with Q1W or Q2W cetuximab were modeled using a population exposure–tumor size (TS) model linked to overall survival (OS); exposure was derived from a previously established population pharmacokinetic model. A semi-mechanistic TS model adapted from the Claret model incorporated killing rate proportional to cetuximab area under the concentration-time curve over 2 weeks (AUC) with Eastern Cooperative Oncology Group (ECOG) status as covariate on baseline TS. The OS was modeled with Weibull hazard using ECOG, baseline TS, primary tumor location, and predicted percent change in TS at 8 weeks as covariates. Model-based simulations revealed indistinguishable early tumor shrinkage and survival between Q2W vs. Q1W cetuximab. CTS evaluated OS non-inferiority (predefined margin of 1.25) in 1,000 trials, each with 2,000 virtual patients receiving Q2W or Q1W cetuximab (1:1), and demonstrated non-inferiority in 94% of cases. Taken together, these analyses provide model-based evidence for clinical non-inferiority of Q2W vs. Q1W cetuximab in mCRC with potential benefits to patients and healthcare providers.

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来源期刊
CiteScore
12.70
自引率
7.50%
发文量
290
审稿时长
2 months
期刊介绍: Clinical Pharmacology & Therapeutics (CPT) is the authoritative cross-disciplinary journal in experimental and clinical medicine devoted to publishing advances in the nature, action, efficacy, and evaluation of therapeutics. CPT welcomes original Articles in the emerging areas of translational, predictive and personalized medicine; new therapeutic modalities including gene and cell therapies; pharmacogenomics, proteomics and metabolomics; bioinformation and applied systems biology complementing areas of pharmacokinetics and pharmacodynamics, human investigation and clinical trials, pharmacovigilence, pharmacoepidemiology, pharmacometrics, and population pharmacology.
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