The treatment of
cancers with
chemotherapy is frequently limited by side effects. The effectiveness may be improved by the use of
monoclonal antibodies to deliver
cytotoxic agents to
cancer cells while limiting exposure to normal tissues. The use of
antibody-drug conjugates (ADCs) is one such strategy: a
drug connected by a linker to an antibody specific for a
tumor antigen is the basic makeup of an ADC. Overexpression and amplification of HER2 is associated with clinically aggressive breast
cancers, and the use of
trastuzumab to target HER2 has been highly effective. That said, most patients with HER2-positive metastatic
breast cancer will eventually have
disease progression during targeted
therapy.
Trastuzumab emtansine (T-DM1) is a novel ADC that combines the humanized antibody
trastuzumab and the potent antimicrotubule agent T-DM1 (derivative of
maytansine) using a unique and highly stable linker. The potential of
maytansine was found in the 1970s with clinical responses noted against
breast cancer; however, substantial toxicity prohibited further development. DM1 possesses in vitro cytotoxicity 10 to 200 times greater than that of
taxanes and
vinca alkaloids. A phase I trial of T-DM1 for patients with heavily pretreated HER2-positive
breast cancer determined a recommended dose of 3.6 mg per kilogram delivered every 3 weeks. Responses were seen in multiple patients. T-DM1 was then studied in phase II trials of patients with HER2-positive metastatic
breast cancer. In a studies of 112 and 110 patients in whom disease had progressed during HER2-directed
therapy, T-DM1 was associated with objective response rates of 26% and 34%, respectively. The agent was well tolerated in both trials, with most toxicities being grade 1 and 2, and no
bleeding episodes or
cardiac events occurring. Additional phase II and III trials are now evaluating T-DM1 in the first-line setting. In one such trial, T-DM1 was compared with standard dosing of
trastuzumab every 3 weeks plus
docetaxel every 3 weeks. Objective response rates were comparable and grade 3 or4 adverse events were substantially reduced in the T-DM1 arm. The anticipated selective activity and reduction in side effects were thus noted. Randomized multicenter phase III trials are ongoing, including the EMILIA trial, an open-label trial of T-DM1 compared with the U.S. Food &
amp;
Drug Administration-approved regimen of
capecitabine plus
lapatinib. The results of studies completed to date suggest T-DM1 is active in patients who have
cancer resistant to
trastuzumab-based combinations.