The pivotal phase III EMILIA trial evaluated the use of ado-trastuzumab emtansine (T-DM1) in comparison with capecitabine and lapatinib for women with HER2-positive locally advanced or metastatic breast cancer. The study showed a 5.6-month improvement in overall survival, says Kim Blackwell, MD. Based on evidence from the study, the FDA approved T-DM1 for the treatment of patients with HER2-positive metastatic breast cancer in February 2013. Although no women enrolled in the EMILIA study had received pertuzumab, the therapeutic index is still quite strong for the use of T-DM1, notes Blackwell, as there were very few chemotherapy-related side effects.

The mechanism of one of the T-DM1 side effects, thrombocytopenia, involves gamma receptor binding. The gamma receptor is differentially expressed based on ethnicity, Blackwell suggests. It is more highly expressed in the Asian population, explaining some of the data that indicate the thrombocytopenic events may be more common in Asian individuals. Blackwell mentions it is difficult to imagine not using T-DM1 in a second-line setting. Richard Finn, MD, notes that T-DM1’s mechanism appears to be independent of signal transduction, and that many of these agents are aimed at overcoming HER2-resistance.

Lee Schwartzberg, MD, explains that clinicians must sometimes rebiopsy patients to prove HER2 status, even if a prior test was negative. Schwartzberg recounts an instance when his practice rebiopsied a patient on her third line of therapy, and she appeared to be HER2-positive. The patient responded to therapy with T-DM1. The efficacy of HER2-targeted therapies requires strenuous testing to ensure the most accurate results.