Karmanos Cancer Institute, Detroit, Michigan, USA.
Clin Cancer Res. 2011 Oct 15;17(20):6437-47. doi: 10.1158/1078-0432.CCR-11-0762.
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.
曲妥珠单抗-美坦新偶联物（T-DM1）是一种人表皮生长因子受体 2（HER2）靶向抗体-药物偶联物，由曲妥珠单抗、稳定的硫醚连接子和有效力的细胞毒药物 DM1（美登素衍生物）组成，目前正在开发用于治疗 HER2 阳性癌症。在临床前研究中对 T-DM1 进行了广泛分析，结果表明，T-DM1 结合了 DM1 和曲妥珠单抗的不同作用机制，在曲妥珠单抗和拉帕替尼耐药的实验模型中具有抗肿瘤活性。临床研究显示，T-DM1 具有一致的药代动力学特征，且系统暴露于游离 DM1 最小，多次给予 T-DM1 后无 DM1 蓄积的证据。虽然在群体药代动力学分析中，有一些协变量显示会影响 T-DM1 暴露和清除的个体间变异性，但它们对 T-DM1 暴露的影响程度无临床意义。T-DM1 作为单药以及与紫杉醇、多西他赛和帕妥珠单抗联合治疗的 I 期和 II 期临床试验显示，该药在 HER2 阳性转移性乳腺癌患者中具有临床活性和良好的安全性。两项 T-DM1 的随机 III 期临床试验正在招募患者：EMILIA（NCT00829166）正在评估 T-DM1 与拉帕替尼联合卡培他滨相比的疗效，而 MARIANNE（NCT01120184）正在评估 T-DM1 联合安慰剂与 T-DM1 联合帕妥珠单抗与曲妥珠单抗联合紫杉烷类药物相比的疗效。T-DM1 的其他联合用药（例如与 GDC-0941 的联合）以及其他疾病治疗领域（早期 HER2 阳性乳腺癌）也正在研究中。人们急切期待来自这些 III 期临床试验和其他 T-DM1 药物研究的数据。
