ASCOA first-in-class HER2 antibody-drug conjugate may represent an effective new strategy in breast cancer therapy, according to phase I data that attracted much attention at the 43rd Annual Meeting of the American Society of Clinical Oncology (abstract 1042).
The investigational agent, trastuzumab-DM1 (T-DM1), is designed to combine the anti-tumor activity of trastuzumab with a means of delivering highly potent chemotherapy directly into HER2-expressing cells.
DM-1 (also known as maytansine) is an inhibitor of tubulin polymerization, binding tubulin competitively with vinca alkaloids. Compared with drugs like vincristine, however, it is 20 to 100 times more potent, said principal investigator Murali Beeram, MD, of the Institute for Drug Development, San Antonio.
"DM-1 was developed in 1975 but was found to be too toxic for standard chemotherapy," Dr. Beeram said. "We tagged it in a very small amount to the trastuzumab molecule with a linker. The linker provides a stable bond between the two agents that is designed to prolong exposure and reduce the toxicity of T-DM1. We are, in essence, sending a chemotherapy payload into the cell via the antibody. We get a twofold effectan increase in the efficacy of trastuzumab and direct delivery of the cytotoxic agent, which reduces treatment toxicity."
Dr. Beeram and colleagues presented data from 18 HER2-positive metastatic breast cancer patients who progressed after a trastuzumab-containing regimen. In addition to prior treatment with trastuzumab, these patients had received multiple prior chemotherapy regimens (median, 7.5).
Five dose levels of the immunoconjugate were evaluated: 0.3 to 4.8 mg/kg given intravenously every 3 weeks.