T-DM1 “Smart Bomb” Hits Breast Cancer Targets

Antibody–drug conjugate extends progression-free survival in patients with HER2-positive disease.

Women with HER2-positive locally advanced or metastatic breast cancer who were previously treated with a taxane and trastuzumab showed significant improvement when treated with the antibody–drug conjugate (ADC) trastuzumab emtansine (T-DM1; Genentech) in a phase III randomized study comparing T-DM1 with the standard therapy of capecitabine (Xeloda; Genentech) and lapatinib (Tykerb; GlaxoSmithKline).

The ADC extended median progression-free survival (PFS) from 6.4 to 9.6 months in the international EMILIA study, reported at the annual meeting of the American Society of Clinical Oncology on June 2 in Chicago.

T-DM1 is among the first in a wave of anticancer ADCs, known informally as “smart bombs” or “armed” or “empowered” antibodies. ADCs connect a targeted monoclonal antibody to a cytotoxic agent using a linker that remains stable in the circulation to prevent systemic release of the cytotoxic drug prior to its arrival at the cancer cell. T-DM1 targets the HER2 protein, which is overexpressed in approximately 20% of breast cancers.

“T-DM1 is a brand new way of treating HER2-positive breast cancer,” said lead study author Kimberly Blackwell, MD, professor of medicine at Duke Cancer Institute in Durham, NC, at Duke University. “It's the first of many antibody–drug conjugates to follow that will link a potent anticancer agent to a targeted delivery system of an antibody.”

The experimental drug has 3 components: the monoclonal antibody trastuzumab, the cytotoxic agent DM1, and a linker. Trastuzumab recognizes and selectively binds to HER2 protein on the surface of tumor cells and exhibits anti-HER2 activity. The attached cytotoxic DM1, a derivative of the potent antimitotic maytansine, was shown in preclinical studies to be to 270-fold more potent than the anticancer agent paclitaxel, and up to 3 orders of magnitude more potent than the agent doxorubicin. The nonreducible linker binds the two together until they enter the HER2-overexpressing cells.

In the EMILIA study, 980 patients were split evenly between 2 treatment arms, receiving either T-DM1 or capecitabine plus lapatinib (a regimen known as XL), every 3 weeks until their disease progressed or they experienced unmanageable toxicity.

The improvement in median PFS for patients receiving T-DM1, compared with XL, was determined to be statistically significant. After 2 years, 65.4% of the T-DM1 patients were alive, compared with 47.5% of the XL patients. This difference did not meet the trial's predetermined statistical survival threshold for the first analysis, and a second survival analysis is planned.

Safety and other secondary endpoints, such as time to symptom progression, favored patients who received T-DM1, and these patients also showed significantly fewer treatment-related toxicities.

Overall, “the EMILIA study really examined a completely new way of treating HER2-positive breast cancer,” said Blackwell.