Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Novartis Pharma AG, Basel, Switzerland.
J Clin Pharmacol. 2023 Dec;63(12):1359-1370. doi: 10.1002/jcph.2310. Epub 2023 Aug 1.
Ribociclib in combination with endocrine therapy (ET) is a globally approved treatment option for patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) and has demonstrated significantly improved overall survival (OS) in 3 phase 3 clinical trials. To justify the dose regimen and dose modification scheme for patients with ABC, the pharmacokinetic (PK), safety, and efficacy data of ribociclib were analyzed. The data of several phase 1-3 clinical studies were pooled and analyzed to characterize the relationship between exposure (dose or PK) and efficacy (progression-free survival (PFS), time to response, and OS) or safety (neutropenia and QT interval prolongation). The exposure-efficacy analysis showed no apparent relationship between ribociclib exposure and efficacy (PFS and OS), and efficacy analysis by dose reduction showed that patients with ABC continued to benefit from the treatment following dose reduction, supporting the starting dose of 600 mg as well as dose reductions to 400 and 200 mg. The exposure-safety analysis showed that neutropenia and QT prolongation are related to ribociclib exposure that can be effectively managed by individualized dose modification (dose reduction/interruption). Collective evidence from the exposure-response analyses for efficacy and safety support the use of ribociclib in combination with ET partners at the starting dose of 600 mg, and also the effectiveness of individualized dose reductions in managing safety, while maintaining efficacy, in patients with HR+/HER2- ABC. This analysis illustrates the utility of quantitative assessment in justifying dose selection and dose modification for oncology medicines.
来曲唑联合内分泌治疗（ET）是一种全球批准的激素受体阳性（HR+）/人表皮生长因子受体 2 阴性（HER2-）晚期乳腺癌（ABC）的治疗选择，在 3 项 3 期临床试验中显示出显著改善的总生存期（OS）。为了证明 ABC 患者的剂量方案和剂量调整方案合理，对来曲唑的药代动力学（PK）、安全性和疗效数据进行了分析。对几项 1-3 期临床研究的数据进行了汇总和分析，以描述暴露（剂量或 PK）与疗效（无进展生存期（PFS）、反应时间和 OS）或安全性（中性粒细胞减少和 QT 间期延长）之间的关系。暴露-疗效分析显示来曲唑暴露与疗效（PFS 和 OS）之间没有明显的关系，剂量减少的疗效分析表明，ABC 患者在剂量减少后继续从治疗中获益，支持起始剂量为 600mg 以及剂量减少至 400mg 和 200mg。暴露-安全性分析表明，中性粒细胞减少和 QT 间期延长与来曲唑暴露有关，通过个体化剂量调整（剂量减少/中断）可以有效管理。疗效和安全性的暴露-反应分析的综合证据支持来曲唑联合 ET 伙伴在起始剂量为 600mg 时的使用，以及在维持疗效的同时，个体化剂量减少在管理安全性方面的有效性，用于 HR+/HER2-ABC 患者。这项分析说明了定量评估在为肿瘤药物选择剂量和调整剂量方面的实用性。
