Adjuvant T-DM1 for Early HER2+ Breast Cancer Demonstrates Low Recurrence Rate

The first reported data for adjuvant ado-trastuzumab emtansine in early HER2-positive breast cancer showed high rates of disease control in a randomized trial designed to compare toxicities with trastuzumab and paclitaxel.

Sara Tolaney, MD,  Dana-Farber Cancer Institute

Sara Tolaney, MD, Dana-Farber Cancer Institute

Sara Tolaney, MD

The first reported data for adjuvant T-DM1 (Kadcyla) in early HER2-positive breast cancer showed high rates of disease control in a randomized trial designed to compare toxicities with trastuzumab (Herceptin) and paclitaxel.

Postoperative T-DM1 led to a 3-year disease-free survival (DFS) of 97.7% and 3-year recurrence-free interval (RFI) of 99.1%. Patients with hormone receptor (HR)-positive or HR-negative cancer had similar DFS.1

The 2 treatment arms did not differ with respect to the coprimary endpoint of incidence of clinically relevant toxicity (CRT).

"This represents the first report of patients receiving T-DM1 monotherapy for adjuvant treatment of stage I HER2-positive breast cancer," said Sara Tolaney, MD, MPH, of Dana-Farber Cancer Institute in a presentation at the 2019 San Antonio Breast Cancer Symposium (SABCS). "T-DM1 was associated with very few recurrences in the study population. Longer follow-up is needed in a population with predominately hormone receptor-positive disease."

"No difference was seen in the overall incidence of clinically relevant toxicities between the 2 arms, but there were differences in toxicity profiles between T-DM1 and trastuzumab-paclitaxel," added Tolaney, who serves as the associate Director of the Susan F. Smith Center for Women's Cancers and director of Clinical Trials, Breast Oncology at Dana-Farber Cancer Institute. "Given the low event rate seen in this trial, T-DM1 may be an alternative to trastuzumab-paclitaxel for select patients with stage I HER2-positive disease who are concerned about specific trastuzumab-paclitaxel side effects and understand the potential T-DM1 toxicities."

Further evaluation of shorter-duration therapy with T-DM1, followed by trastuzumab, should be considered, said Tolaney.

The rationale for the ATEMPT trial (NCT01853748), came from recognition that some stage I HER2-positive breast cancers have a sufficiently high risk of recurrence to justify adjuvant therapy.2 Trastuzumab and paclitaxel (TH) is associated with a 7-year DFS of 93% in patients with node-negative HER2-positive breast cancer ≤3 cm.3,4

Several studies have shown that T-DM1 has activity in patients with metastatic HER2-positive breast cancer and residual disease after neoadjuvant HER2-directed therapy, Tolaney noted. Additionally, T-DM1 is associated with less toxicity as compared with chemotherapy and trastuzumab.

Investigators in the ATEMPT trial sought to determine whether T-DM1 has a clinically acceptable event rate in patients with stage I HER2-positive breast cancer and whether T-DM1 is associated with less clinically relevant toxicity (CRT) as compared with TH.

The coprimary endpoints were 3-year DFS in the T-DM1 arm and compared incidence of CRTs between T-DM1 and TH. CRTs were defined as grade ≥3 nonhematologic toxicity, grade ≥2 neurotoxicity, grade ≥4 hematologic toxicity, febrile neutropenia, and any toxicity requiring dose delay or discontinuation.

For evaluation of DFS in the T-DM1 arm, the trial had statistical power to distinguish between 3-year failure rates of 9% versus 5%. For the comparison of CRTs, the trial was powered to detect a 40% difference in incidence.

The study population included 497 patients, randomized 2:1 to T-DM1 or TH. Baseline characteristics were balanced between the 2 treatment groups. The patients had a median age of 56, 75% had HR-positive breast cancer, and 73% had 3+ HER2 expression status as determined by fluorescence in situ hybridization.

The trial met the coprimary endpoint of 3-year DFS (P <.0001). The overall DFS of 97.7% included 97.5% in patients with HR-positive disease and 98.5% in HR-negative disease. DFS by tumor size was 98.5% for patients with tumors <1 cm and 97.1% for those with tumors ≥1 cm. DFS events consisted of 7 recurrences (2 ipsilateral, 3 contralateral HER2 negative, and 2 distant) and 3 deaths unrelated to breast cancer.

Although the trial did not compare DFS between the treatment groups, the TH arm had a 3-year DFS of 92.8%. The 7 DFS events consisted of 4 ipsilateral recurrences, 1 new contralateral primary breast cancer, and 2 distant recurrences.

With regard to CRTs, the overall incidence was 46% in both arms. The only notable differences were a higher incidence of neurotoxicity with TH (23% vs 11%) and more toxicity-related early discontinuations with T-DM1 (17% vs 6%).

Overall, 23.5% of patients in the T-DM1 arm discontinued, 17% because of toxicity. Tolaney noted that two thirds of patients who discontinued early for toxicity received additional treatment with trastuzumab. The rate of protocol-mandated discontinuation for toxicity was 9%.

Rates of symptomatic congestive heart failure were 0.8% with T-DM1 and 0.9% with TH. Rates of asymptomatic decline in left ventricular ejection fraction of at least 15% were 1.3% with T-DM1 and 6.1% with TH.


  1. Tolaney SM, Hu J, Dang C, et al. TBCRC 033: A randomized phase II study of adjuvant trastuzumab emtansine (T-DM1) vs paclitaxel (T) in combination with trastuzumab (H) for stage I HER2-positive breast cancer (BC) (ATEMPT). Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract GS1-05.
  2. Gonzalez-Angulo AM, Litton JK, Broglio KR, et al. High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive, node-negative tumors 1 cm or smaller. J Clin Oncol. 2009;27(34):5700-5706. doi: 10.1200/JCO.2009.23.2025.
  3. Tolaney SM, Barry WT, Dang C, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med. 2015;372(2):134-14. doi: 10.1056/NEJMoa1406281.
  4. Tolaney SM, Guo H, Pernas S, et al. Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2—positive breast cancer. J Clin Oncol. 2019;37(22):1868-1875. doi: 10.1200/JCO.19.00066.
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