Clinical and pharmacological characteristics of trastuzumab emtansine, an antibody-drug conjugate in the treatment of HER2+ breast cancer

摘要

Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor 2 (HER2) targeted antibody-drug - trastuzumab (T) - conjugated to an antimicrotubular agent, derivative of maytansine (DM1), through a stable thioether linker (MCC). Preclinical analysis showed that T-DM1 combines the distinct mechanisms of trastuzumab and DM1, and shows an antitumor activity in experimental models resistant to trastuzumab and lapatinib. Phase I and II trials showed a clinical efficacy of T-DM1 with a favourable safety profile in HER2-positive locally advanced or metastatic breast cancers. T-DM1 pharmacokinetics profile was predictable and well characterized; pharmacokinetics properties were consistent among all clinical studies. Exposure to free DM1 was minimal, with no evidence of accumulation after repeated T-DM1 administration. Recently, efficacy and safety of T-DM1 were confirmed in a phase III study (EMILIA) evaluating TDM1 vs. lapatinib plus capecitabine, with a significant benefit on progression-free survival, overall survival, and the tolerance profile. The results from further phase III studies evaluating T-DM1 single agent or in association with pertuzumab as first line treatment in HER2-positive locally advanced or metastatic breast cancers are awaited.