Abstract
Trastuzumab is a monoclonal antibody targeted against the HER2 tyrosine kinase receptor. Although trastuzumab is a very active agent in HER2-overexpressing breast cancer, the majority of patients with metastatic HER2-overexpressing breast cancer who initially respond to trastuzumab develop resistance within 1 year of initiation of treatment and, in the adjuvant setting, progress despite trastuzumab-based therapy. The antibody-drug conjugate trastuzumab-DM1 (T-DM1) was designed to combine the biological activity of trastuzumab with the targeted delivery of a highly potent antimicrotubule agent, DM1 (N-methyl-N-[3-mercapto-1-oxopropyl]-l-alanine ester of maytansinol), a maytansine derivative, to HER2-overexpressing breast cancer cells. T-DM1 is the first antibody-drug conjugate with a nonreducible thioether linker in clinical trials. Phase I and 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 awaiting final results; the EMILIA trial is evaluating T-DM1 compared with lapatinib plus capecitabine, and early positive results have been reported. The MARIANNE trial is evaluating T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane. Here, we summarize evidence from clinical studies and discuss the potential clinical implications of T-DM1.
Highlights
Cytotoxic drugs and therapeutic monoclonal antibodies represent two major classes of agents currently used for cancer treatment
One particular method is targeting drug carriers such as antibodies; this is the objective of antibody-drug conjugates (ADCs), in which cytotoxic drugs are attached via chemical linkers to antibodies that recognize cancer cell antigens and deliver the cytotoxic drug only to the cells of interest
We summarize evidence from clinical studies and discuss the potential impact of the use of an HER2 ADC in the treatment of HER2overexpressing breast cancer
Summary
Cytotoxic drugs and therapeutic monoclonal antibodies represent two major classes of agents currently used for cancer treatment. A phase I study in patients (N = 24) with HER2 metastatic breast cancer whose disease had progressed on earlier trastuzumab-based therapy assessed the safety and tolerability of T-DM1 administered every 3 wks by intravenous infusion over 30–90 min (Table 1) [41].
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