The US Food and Drug Administration (FDA) recently approved a new type of treatment that links trastuzumab with a powerful cytotoxic agent for advanced HER2-positive breast cancer.1

Combining this agent, called an antibody-drug conjugate (ADC), is on the cutting edge of cancer treatment research, with only one other such conjugate currently in use.2 The newly approved agent, trastuzumab emtansine (TDM-1), links trastuzumab with the extremely potent microtubule-inhibiting agent DM-1, a derivative of maytansine.2,3

The challenge in developing an ADC is to avoid triggering intolerable systemic toxicity by ensuring that the cytotoxic agent is delivered into the tumor cell before the complex is metabolized. TDM-1 accomplishes this by using a nonreducible thioether linkage that prevents DM-1 from being released until the complex has been internalized by an HER2-positive tumor cell.2

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In single-arm phase II studies, TDM-1 produced objective responses in women with metastatic breast cancer (MBC) whose disease had progressed on trastuzumab-based regimens. Progression-free survival (PFS) of 4.6 months and 6.9 months was reported in these studies.4,5 FDA approval was based on results of the phase III EMILIA study, published last November in the New England Journal of Medicine. In this study, 991 women with HER2-positive MBC that had progressed on treatment with trastuzumab and a taxane were randomly assigned to treatment with TDM-1 or lapatinib plus capecitabine, a recommended option for women with HER2-positive MBC refractory to regimens containing trastuzumab plus an anthracycline or taxane.3,6

Treatment with TDM-1 versus lapatinib plus capecitabine prolonged PFS (the primary endpoint) and overall survival. Women receiving TDM-1 were 35% less likely to have progressed (P<0.001) and 32% less likely to have died from any cause (P<0.001).3 Consistent with findings in phase II studies, the most common grade 3 or 4 adverse event with TDM-1 was thrombocytopenia; others included fatigue and elevated transaminases.3-5 Overall, TDM-1 was also associated with a lower rate of grade 3 or 4 adverse events compared to lapatinib plus capecitabine.  

While the FDA approval specifies that TDM-1 is for HER2-positive advanced breast cancer patients previously treated with trastuzumab and a taxane, TDM-1 also is being investigated in treatment-naïve MBC. In newly published results of a phase II study, single-agent TDM-1 was associated with longer PFS and a better safety profile than combined trastuzumab/docetaxel.7 A three-arm phase III study is currently evaluating TDM-1 plus pertuzumab or placebo versus trastuzumab plus a taxane for treatment-naïve MBC.2

Pertuzumab and trastuzumab have different mechanisms of action and may potentially produce better responses when used as in combination than either agent alone. At present, combination pertuzumab/trastuzumab/taxane therapy is the preferred treatment approach for HER2-positive MBC according to the National Comprehensive Cancer Network guidelines.6 Will TDM-1 plus pertuzumab improve patient outcomes and trump the current recommended regimen? Only time and more clinical evaluations can tell.

For the approximately 20% of women whose breast cancer overexpresses the HER2 receptor, trastuzumab has become a crucial part of standard care that reduces recurrence and prolongs survival. Unfortunately, HER2-positive disease usually progresses despite trastuzumab therapy.2 Even in the setting of disease progression, HER2 is overexpressed and remains a viable target; in fact, women whose disease has progressed on a trastuzumab regimen still derive benefit from continuing trastuzumab therapy and it is recommended that they do so.6 TDM-1, on the other hand, may provide the continued benefit of trastuzumab with the addition of a potent new cytotoxic agent, offering new hope to women whose HER2-positive MBC has proven refractory to earlier treatment.

TDM-1 is administered intravenously on a 21-day schedule. Its approved label includes a boxed warning about liver toxicity, cardiac toxicity, death, and severe birth defects; it should be avoided during pregnancy. The drug will be sold by Genentech Inc. under the brand name KADCYLA.1,3


1. Food and Drug Administration. FDA approves new treatment for late-stage breast cancer. Available from: Accessed February 23, 2013.

2. Barginear MF, John V, Budman DR. Trastuzumab-DM1: a clinical update of the novel antibody-drug conjugate for HER2-overexpressing breast cancer. Mol Med. 2012;18:1473-1479.

3. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783-1791.

4. Krop IE, LoRusso P, Miller KD, et al. A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor to positive metastatic breast cancer treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2012;10(30):3234-3241.

5. Burris HA III, Rugo HS, Vukelja SJ, et al. Phase II study of the antibody drug conjugate trastuzumab DM-1 for treatment of human epidermal growth factor receptor 2–positive breast cancer after prior HER2-directed therapy. J Clin Oncol. 2011;29(4):398-405.

6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V1.2013. Available from Accessed February 26, 2013.

7. Hurvitz SA, Dirix L, Kocsis J, et al. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patient with human epidermal growth factor receptor 2–positive metastatic breast cancer. J Clin Oncol. 2013;e pub ahead of print, Feb 4, 2013; doi: 10.1200/JCO.2012.44.9694.