Trastuzumab emtansine is an antibody-drug conjugate comprised of the receptor tyrosine-protein kinase erbB-2 (HER2) antibody trastuzumab, and a derivative of the cytostatic agent maytansinoid DM1, covalently linked by a thiol linker. The drug was developed in an attempt to overcome trastuzumab resistance in patients with HER2-positive breast carcinoma, but it is also of potential use in other HER2-positive cancers. The preclinical antitumor activity of trastuzumab emtansine was established in HER2-positive breast cancer cell lines and murine xenograft models. Preclinically, trastuzumab emtansine was efficacious in HER2-positive cells that were resistant to trastuzumab or lapatinib. Clinically, the drug is well tolerated in most patients, with a predictable pharmacokinetic profile and minimal systemic exposure to free cytotoxic DM1. Unlike with trastuzumab, cardiac toxicity has not been seen in patients receiving trastuzumab emtansine and less adverse events have been reported than with other chemotherapy regimens. Results from a number of phase II studies and early results from a phase III investigation (EMILIA) demonstrated response rates of 25-35% in patients with breast cancer who had previously received trastuzumab. Several phase II and III studies are under way investigating trastuzumab emtansine in combination with other regimens in patients with HER2-positive cancers.
Keywords: Antibody-drug conjugates; Breast cancer therapy; Cytochrome P450 3A4 inhibitors; Trastuzumab emtansine; Trastuzumab-DM1.
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