Trastuzumab Emtansine: A Unique Antibody-Drug Conjugate in Development for Human Epidermal Growth Factor Receptor 2-Positive Cancer
Trastuzumab Emtansine: A Unique Antibody-Drug Conjugate in Development for Human Epidermal Growth Factor Receptor 2-Positive Cancer
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DOI：
10.1158/1078-0432.ccr-11-0762
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发表时间：
2011-10-15
影响因子：
11.5
通讯作者：
Sliwkowski, Mark X.
中科院分区：
文献类型：
--
作者：
LoRusso, Patricia M.;Weiss, Denise;Sliwkowski, Mark X.
曲妥珠单抗emtansine （T-DM1）是一种人表皮生长因子受体（HER2）靶向抗体-药物偶联物，由曲妥珠单抗、稳定的硫醚连接剂和强效细胞毒剂DM1（美坦辛的衍生物）组成，目前正处于HER2阳性癌症的III期开发中。在临床前研究中对T-DM1的广泛分析表明，T-DM1结合了DM1和曲妥珠单抗的不同作用机制，并且在曲妥珠单抗和拉帕替尼耐药实验模型中具有抗肿瘤活性。临床上，T-DM1具有一致的药代动力学特征和最小的全身游离DM1暴露，在重复T-DM1剂量后没有DM1积累的证据。尽管在人群药代动力学分析中，一些协变量被证明会影响T-DM1暴露和清除的个体间变异性，但它们对T-DM1暴露的影响程度与临床无关。T-DM1作为单一药物和与紫杉醇、多西他赛和帕妥珠单抗联合使用的I期和II期临床试验显示，在her2阳性转移性乳腺癌患者中，T-DM1具有临床活性和良好的安全性。两项T-DM1的随机III期试验正在招募患者：EMILIA （NCT00829166）正在评估T-DM1与拉帕替尼+卡培他滨的比较，MARIANNE（NCT01120184）正在评估T-DM1 +安慰剂与T-DM1 +帕妥珠单抗与曲妥珠单抗+紫杉烷的比较。T-DM1的其他组合（例如与GDC-0941联合使用）和其他疾病情况（早期her2阳性乳腺癌）也在研究中。关于t - dm1药物的III期试验和其他研究的数据正在等待中。临床癌症研究；17 (20);6437 - 47。(c) 2011年aacr。
Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor (HER2)-targeted antibody-drug conjugate, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine), in phase III development for HER2-positive cancer. Extensive analysis of T-DM1 in preclinical studies has shown that T-DM1 combines the distinct mechanisms of action of both DM1 and trastuzumab, and has antitumor activity in trastuzumab-and lapatinib-refractory experimental models. Clinically, T-DM1 has a consistent pharmacokinetics profile and minimal systemic exposure to free DM1, with no evidence of DM1 accumulation following repeated T-DM1 doses. Although a few covariates were shown to affect interindividual variability in T-DM1 exposure and clearance in population-pharmacokinetics analyses, the magnitude of their effect on T-DM1 exposure was not clinically relevant. Phase I and phase II clinical trials of T-DM1 as a single agent and in combination with paclitaxel, docetaxel, and pertuzumab have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. Two randomized phase III trials of T-DM1 are recruiting patients: EMILIA (NCT00829166) is evaluating T-DM1 compared with lapatinib plus capecitabine, and MARIANNE(NCT01120184) is evaluating T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane. Additional combinations of T-DM1 (for example, with GDC-0941) and additional disease settings (early-stage HER2-positive breast cancer) are also under investigation. Data from the phase III trials and other studies of T-DM1-containing agents are eagerly awaited. Clin Cancer Res; 17(20); 6437-47. (C) 2011 AACR.