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The Antibody-drug Conjugate Trastuzumab Emtansine (TDM-1) Significantly Prolongs Survival in HER2 Positive Advanced Breast Cancer

15 Oct 2012
Breast cancer
Valentina Guarneri

Amplification of the human epidermal growth factor receptor 2 (HER2) gene and resulting over-expression of the HER2 protein is present in approximately 20% of invasive primary breast cancers. In patients with HER2-positive advanced breast cancer, the anti HER2 antibody trastuzumab is recommended as first-line therapy in combination with non-anthracycline-based chemotherapy.  The dual HER1-HER2 tyrosine kinase inhibitor lapatinib in combination with capecitabine is currently the standard of care for HER2 positive advanced breast cancer after failure of anthracycline, taxanes and trastuzumab. This scenario is however likely to change in the near future.

Antibody-drug conjugates are designed to target  the delivery of a highly potent cytotoxic agent to antigen-expressing cells, potentially improving the therapeutic index of the agent. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate which combines the antitumour activity of the trastuzumab with the antimicrotubule agent DM1.

The antibody and the cytotoxic agent are covalently linked via a stable thioether linker, to specifically deliver the antimicrotubule agent in HER2-expressing cells. The safety profile and activity of T-DM I in phase I and II studies were encouraging (Krop IE, J Clin Oncol 2010;  Burris HA, J Clin  Oncol 2011; Krop IE, J Clin Oncol  2012).

In the October issue of the New England Journal of Medicine, the results of the EMILIA randomized Phase III study have been published. In this study, patients with HER2 positive advanced breast cancer and previous exposure to a taxane and trastuzumab were randomly assigned to receive T-DM1 or the combination of lapatinib-capecitabine. The primary end points were progression-free survival (per independent review), overall survival, and safety. 991 patients were enrolled. Patients characteristics were balanced between the two arms. The majority of the patients (68% in the lapatinib-capecitabine and 67% in the T-DM1 arm) had visceral involvement. In both arms, 39% of the patients have received more than 1 line of chemotherapy for metastatic disease. Notably, 16% of the patients in both arms have failed trastuzumab for early disease only (disease-free interval of less than 6 months from the completion of adjuvant or neo-adjuvant trastuzumab).  Treatment with TDM-1 resulted in a significant prolongation of median progression free survival (9.6 months versus 6.4 months observed with lapatinib-capecitabine, HR 0.65, P<0.001). At the second interim analysis, the  median overall survival crossed the stopping boundary for efficacy (30.9 months vs. 25.1 months; HR 0.68; P<0.001). Moreover, treatment with TDM-1 resulted in less Grade 3 or 4 adverse events (41% versus 57% with lapatinib capecitabine). In particular, treatment with lapatinib-capecitabine resulted in a higher incidence of diarrhoea, nausea and vomiting, and palmar-plantar erythrodysesthesia. T-DM1 was associated with higher incidence of increased serum aminotransferase levels and thrombocytopenia. These events were however mostly low grade, and generally manageable with protocol-specified dose adjustment. The rate of treatment interruptions due to adverse events were 7.8% for lapatinib, 9.4 for capecitabine, and 5.9 for T-DM1. In summary, T-DM1 significantly prolonged progression-free and overall survival in HER2-positive advanced breast cancer patients who have failed previous trastuzumab-based therapy. Notably, this improvement is achieved along with a reduction in clinically relevant adverse events. These results therefore provide clinical confirmation that the selective intracellular delivery of the cytotoxic agent in HER2-positive cancer cells improves the therapeutic index minimizing the exposure of normal tissue.
On these premises, T-DM1 is likely to become the new standard for HER2 positive advanced breast cancer who failed trastuzumab-based therapy.

Last update: 15 Oct 2012

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