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T-DM1 Now Standard for Heavily Pretreated HER2+ Breast Cancer

Gina Columbus @ginacolumbusonc
Published: Monday, Mar 28, 2016

Dr. Hans Wildiers

Hans Wildiers, MD, PhD

Although T-DM1 (ado-trastuzumab emtansine; Kadcyla) is already approved by the FDA as a treatment for patients with HER2-positive breast cancer previously treated with trastuzumab (Herceptin) and a taxane, findings from the TH3RESA study1 also support the regimen as a standard of care for heavily pretreated patients, explains Hans Wildiers, MD.

In the open-label phase III TH3RESA trial, 602 patients with progressive HER2-positive advanced breast cancer were randomized in a 2:1 ratio to T-DM1 (n = 404) at 3.6 mg/kg IV every 3 weeks or physician’s choice of treatment (n = 198).

All of the women in the study had progressed on 2 or more HER2-targeted therapies, including trastuzumab and lapatinib (Tykerb) in the advanced setting, and a taxane in any setting. More than half of patients in both arms had received 4 or more prior regimens for advanced breast cancer.

Updated results from TH3RESA presented at the 2015 San Antonio Breast Cancer Symposium showed that T-DM1 reduced the risk of death by 32% and improved median overall survival (OS) by almost 7 months compared with physician's choice of therapy.

At a median follow-up of 30.5 months (338 events), median OS was 22.7 months with T-DM1 versus 15.8 months with physician’s choice (HR, 0.68; 95% CI, 0.54-0.85; P = .0007). The OS benefit was observed regardless of age, visceral involvement, hormone receptor status, number of prior regimens, and physician’s selection of therapy.

Median progression-free survival (PFS) was 6.2 months with T-DM1 versus 3.3 months in the control arm (HR, 0.528; 95% CI, 0.422-0.661; P <.0001).

The TH3RESA findings further confirm those of the phase III EMILIA study,2 which was the basis for the FDA’s approval of T-DM1. In the study, patients with previously treated HER2-positive advanced breast cancer were randomized to receive either T-DM1 or a combination of lapatinib and capecitabine.

Patients in the EMILIA study who received T-DM1 experienced PFS and OS improvements as well as less toxicity than the lapatinib and capecitabine combination.

In an interview with OncLive, Wildiers, lead author on the TH3RESA study and a professor of Medical Oncology at KU Leuven in Belgium, provides an overview of TH3RESA and discusses the trial’s significance in the field of HER2-positive breast cancer.

OncLive: What was the design of the phase III TH3RESA study?

Wildiers: The TH3RESA study is a randomized study comparing T-DM1 versus a treatment of physician’s choice in patients with HER2-positive metastatic breast cancer. T-DM1 is an antibody-drug conjugate composed of trastuzumab, stably linked to a DM1 cytotoxic microtubule inhibitor. T-DM1 is already approved in HER2-positive metastatic breast cancer.

This is based on the EMILIA study, where T-DM1 showed a PFS and OS benefit in second-line therapy after receiving a taxane and trastuzumab.

The TH3RESA study was developed to evaluate T-DM1 in a more advanced setting, where more than half of the patients had received 4 or more prior regimens for advanced breast cancer.

After a median follow-up of 30 months, OS improved by 6.9 months. It went from 15.8 months for patients in the control arm to 22.7 months for those in the T-DM1 arm, which was highly significant. Because of that effect, at least 50% of patients in the control arm crossed over to T-DM1 at progression.

What are the clinical implications of these findings?

The TH3RESA study confirms the EMILIA study. Both trials show that, if you use T-DM1 in patients with HER2-positive metastatic breast cancer who received a taxane and trastuzumab, T-DM1 is the preferred regimen in that setting.

This is also why the NCCN guidelines exactly state that T-DM1 is the preferred regimen in this setting.

Were there any concerning toxicities with T-DM1?

T-DM1 has a favorable safety profile. There was slightly more thrombocytopenia in the T-DM1 arm. However, other toxicities, such as febrile neutropenia, diarrhea, and nausea, were all clearly higher in the control arm.

Importantly, we achieved a nearly 7-month overall survival benefit with less toxicity.


  1. Wildiers H, Kim S-B, Gonzalez-Martin A, et al. Trastuzumab emtansine improves overall survival versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer: Final overall survival results from the phase 3 TH3RESA study. Presented at: 2015 San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract S5-05.
  2. 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.

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