Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
Office of Biostatistics, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
Clin Pharmacol Ther. 2014 May;95(5):558-64. doi: 10.1038/clpt.2014.24. Epub 2014 Jan 31.
Exposure-response (E-R) analyses for ado-trastuzumab emtansine (T-DM1, Kadcyla) were performed using data from a randomized, active control (lapatinib plus capecitabine) trial in patients with human epidermal growth factor 2-positive metastatic breast cancer. Kaplan-Meier survival analyses stratified by T-DM1 trough concentration on day 21 of cycle 1 (Cmin,C1D21) were performed for overall survival (OS) and progression-free survival (PFS). E-R analyses indicated that after adjusting for baseline risk factors, higher T-DM1 exposure is associated with improved efficacy. T-DM1-treated patients with Cmin,C1D21 lower than the median value had values of OS and PFS comparable to those of the active control arm. The percentage of patients who received T-DM1 dose adjustments was similar across the exposure range and was lower than that of the active control arm. Our findings suggest that there may be an opportunity to optimize Kadcyla dose in the patient subgroup with low T-DM1 exposure for improved efficacy with acceptable tolerability.
采用曲妥珠单抗-美坦新偶联物（T-DM1，Kadcyla）治疗人表皮生长因子 2 阳性转移性乳腺癌的一项随机、阳性对照（拉帕替尼加卡培他滨）试验的数据进行了暴露-反应（E-R）分析。对第 1 周期第 21 天（C1D21）T-DM1 谷浓度进行分层的 Kaplan-Meier 生存分析用于总生存期（OS）和无进展生存期（PFS）。E-R 分析表明，在调整基线风险因素后，更高的 T-DM1 暴露与疗效改善相关。T-DM1 治疗组 C1D21 低于中位数的患者的 OS 和 PFS 值与阳性对照臂相当。在整个暴露范围内，接受 T-DM1 剂量调整的患者比例与阳性对照臂相似，且低于阳性对照臂。我们的研究结果表明，对于 T-DM1 低暴露的患者亚组，可能有机会优化 Kadcyla 剂量，以提高疗效并具有可接受的耐受性。
