T-DM1 is approved by the US Food and Drug Administration (FDA) for patients with HER2-positive metastatic breast cancer who had previously been treated with trastuzumab and a taxane, separately or in combination; it is the only antibody-drug conjugate approved as a single agent for the treatment of breast cancer.1

The KATHERINE trial was an international, phase 3, randomized, open-label study of 1486 patients with HER2-positive early breast cancer (stages I-III) who had residual disease in the breast or axilla after neoadjuvant chemotherapy and HER2-targeted therapy. Patients were randomly assigned to receive T-DM1 or trastuzumab postoperatively for 14 cycles.1

At the interim analysis, invasive disease or death occurred in 91 patients (approximately 12%) in the T-DM1 group and in 165 patients (22.2%) in the trastuzumab group; an impressive improvement of 11.3% in the rate of invasive disease-free survival. At 3 years, the percentage of patients who were free of invasive disease in the T-DM1 group was 88.3% vs 77% in the trastuzumab group (hazard ratio [HR], 0.50; 95% CI, 0.39-0.64, P <.001).1

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Treatment with T-DM1 resulted in a higher incidence of side effects of all grades compared with trastuzumab, and more serious side effects occurred with T-DM1 than trastuzumab (12.7% vs 8.1%, respectively). More patients discontinued T-DM1 (18.0% vs 2.1%) before the end of the trial.1 The most common grade 3 events in the T-DM1 group were decreased platelets and hypertension. One patient in the T-DM1 group died from intracranial hemorrhage after a fall associated with treatment-related thrombocytopenia.

The results of the trial are clinically meaningful, and suggest that T-DM1 monotherapy may be indicated in patients with HER2 disease, instead of combination chemotherapy with trastuzumab.

The KATHERINE trial showed that switching from HER2-targeted therapy to single agent T-DM1 after neoadjuvant therapy, and extending therapy with HER2-targeted therapy beyond 1 year of trastuzumab, both improved outcomes.1,5,6

In his editorial to the NEJM, Dr Hayes suggests that T-DM1 could be the drug of choice for patients with residual disease. In addition, with the availability of active agents in the early stage, the use of anthracyclines (and their cardiac side effects and future risk of hematologic cancers) can be avoided. In addition, he suggested that T-DM1 has the potential to replace neratinib in the postoperative setting in this patient population. 3

Based on the KATHERINE trial, neoadjuvant therapy with trastuzumab, with or without pertuzumab, may be the new standard of care in patients with newly diagnosed HER2-positive breast cancer. In patients with less than complete pathCR, and stage II or stage III disease, T-DM1 can improve long-term outcomes.3

According to Miguel Martin, MD, professor of medicine at the Complutense University and head of the medical oncology service at the Hospital General Universitario Gregorio Marañón, Madrid, Spain, “T-DM1 is a second opportunity for patients who have not achieved best response with neoadjuvant chemotherapy and targeted HER2 therapy, who are at high risk for recurrence. These patients now have T-DM1, a very active treatment option and a rescue drug. In addition, the KATHERINE trial represents a change in the way we treat HER2-positive breast cancer. For patients with residual disease, T-DM1 should be the preferred option for most patients instead of surgery followed by adjuvant therapy. Identification of additional biomarkers will be required to confirm the efficacy of T-DM1 in the neoadjuvant setting.”7


  1. von Minckwitz G, Huang C-S, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med 2019;380(7):617-628.
  2. Prowell TM, Beaver JA, Pazdur R. Residual disease after neoadjuvant therapy ­­­­— developing drugs for high-risk early breast cancer. N Engl J Med. 2019;380(7):612-615.
  3. Hayes, D. Further progress for patients with breast cancer [editorial]. N Engl J Med. 2019;380(7):676-677.
  4. Teicher BA, Doroshow JH. The promise of antibody drug conjugates [editorial]. N Engl J Med. 2012;367(19):1847-1848.
  5. Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1688-1700.
  6. von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377(2):122-131.
  7. Hurvitz SA, Martin M, Symmans WF, et al. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomized, open-label, multicenter, phase 3 trial. Lancet Oncol. 2018;19(1):115-126.