Abstract
T-DM1 improves survival in patients with HER2-positive metastatic breast cancer.
Major finding: T-DM1 improves survival in patients with HER2-positive metastatic breast cancer.
Concept: T-DM1 combines the anti-HER2 antibody trastuzumab and DM1, a cytotoxic microtubule inhibitor.
Impact: This conjugate specifically targets HER2-expressing tumor cells, thus reducing toxicity.
HER2 amplification occurs in a subset of breast cancers and is associated with poor prognosis. Targeted therapies directed against HER2, including the monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib, provide clinical benefit to patients with HER2-positive advanced breast cancer, particularly when administered with chemotherapeutic agents such as capecitabine or taxanes. An alternative treatment approach is to direct cytotoxic drug delivery to HER2-expressing tumor cells using trastuzumab emtansine (T-DM1), an antibody–drug conjugate consisting of trastuzumab and DM-1, an inhibitor of microtubule assembly; prior phase II trials have shown that T-DM1 has activity in HER2-positive disease. To further assess the efficacy and safety of T-DM1, Verma and colleagues conducted a randomized, open-label phase III trial comparing T-DM1 with the standard combination of lapatinib plus capecitabine in 991 patients with centrally confirmed HER2-positive locally advanced or metastatic breast cancer who had been previously treated with trastuzumab and a taxane. The primary endpoints were progression-free survival (PFS), overall survival (OS), and safety, and key secondary endpoints included objective response rate and timeto-symptom progression. T-DM1 treatment prolonged PFS (9.6 vs. 6.4 months) and enhanced OS (30.9 vs. 25.1 months) compared with lapatinib plus capecitabine. In addition, treatment with T-DM1 resulted in an increased objective response rate (43.6% vs. 30.8%) and a longer duration of response (12.6 vs. 6.5 months). T-DM1 was generally well tolerated, with a lower incidence of grade 3 or 4 adverse events compared with lapatinib plus capecitabine (40.8% vs. 57.0%); the most commonly reported side effects were manageable with dose modification and included thrombocytopenia and elevated serum aminotransferase levels. These findings support the use of T-DM1 as an effective and well-tolerated treatment for patients with metastatic HER2-positive breast cancer.
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