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Adjuvant T-DM1 Improves iDFS in Phase III HER2+ Breast Cancer Trial

Gina Columbus @ginacolumbusonc
Published: Monday, Oct 15, 2018

Dr. Sandra Horning
Sandra Horning, MD
Ado-trastuzumab emtansine (T-DM1; Kadcyla) was found to significantly reduce the risk of invasive disease recurrence or death compared with trastuzumab (Herceptin) as an adjuvant treatment in patients with HER2-positive early breast cancer who have residual disease following neoadjuvant therapy, according to topline findings of the phase III KATHERINE study.

UPDATE 12/5/2018: T-DM1 Likely New Adjuvant Standard in High-Risk HER2+ Breast Cancer

Moreover, no new safety signals with T-DM1 were reported and the safety profile was consistent with prior studies of the agent. Full data will be presented at the 2018 San Antonio Breast Cancer Symposium and will be submitted to the FDA and European Medicines Agency, Genentech (Roche), the developer of the antibody-drug conjugate, stated in a news release.

“We are highly encouraged by these positive results with adjuvant Kadcyla treatment in people with HER2-positive early breast cancer who have residual disease after neoadjuvant therapy,” said Sandra Horning, MD, chief medical officer and head of Global Product Development, Genentech. “We look forward to discussions with regulatory authorities with the goal of bringing this new treatment option to patients as soon as possible.”

KATHERINE (NCT01772472) is an international, multicenter, two-arm, open-label, randomized trial evaluating the efficacy and safety of T-DM1 compared with trastuzumab as an adjuvant treatment in patients with HER2-positive early breast cancer who have pathological invasive residual disease in the breast and/or axillary lymph nodes after neoadjuvant trastuzumab and taxane-based chemotherapy. The primary endpoint of the study is invasive disease-free survival (iDFS), defined as the time from randomization to invasive breast cancer recurrence or death from any cause. Secondary endpoints are disease-free survival and overall survival (OS).

The patient population on the KATHERINE trial includes those with HER2-positive breast cancer who did not achieve a pathological complete response to neoadjuvant therapy. The company stated that this subset of patients is associated with a worse prognosis.

T-DM1 was administered intravenously at 3.6 mg/kg every 3 weeks for 14 cycles while trastuzumab was administered intravenously at 6 mg/kg, also every 3 weeks for 14 cycles.

Patients enrolled on the trial had to be at least 18 years of age, histologically confirmed invasive breast carcinoma, clinical stage T1-4/N0-3/M0 at presentation, completion of preoperative systemic chemotherapy and HER2-directed therapy, an ECOG performance status of 0 or 1, and adequate hematologic, renal, and liver function. Investigators were planning to enroll 1487 patients on the trial.

The FDA approved T-DM1 for patients with metastatic HER2-positive breast cancer who previously received trastuzumab and a taxane, either alone or in combination, in February 2013. The drug also comes with a boxed warning, as it has been associated with liver toxicity, heart toxicity and death, and it is capable of causing severe birth defects.

The approval was based in large part on findings of the phase III EMILIA trial. In that trial, patients with HER2-positive advanced breast cancer, who were previously treated with trastuzumab and a taxane, were randomized to receive either T-DM1 or lapatinib (Tykerb) combined with capecitabine.

After a median follow-up of about 20 months, results showed that those who received T-DM1 had a 32% reduced mortality risk versus patients who received lapatinib/capecitabine (HR; 0.68; 95% CI, 0.55-0.85; P <.001).1 Median OS was 30.9 months for patients who received T-DM1 compared with 25.1 months for patients who received lapatinib and capecitabine.

In final OS results of EMILIA, which were published in Lancet Oncology in June 2017, the median OS was longer with T-DM1 than with lapatinib/capecitabine at 29.9 months (95% CI, 26.3-34.1) versus 25.9 months (95% CI 22.7-28.3), respectively (HR, 0.75; 95% CI, 0.64-0.88).2 Moreover, 136 of 496 patients crossed over from the lapatinib/capecitabine arm to T-DM1 after the second interim OS analysis.


  1. Verma S, Miles D, Gianni L. Updated overall survival results from EMILIA, a phase 3 study of T-DM1 (T-DM1) vs capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC). Paper presented at: 37th European Society for Medical Oncology Congress; September 28-October 2, 2012; Vienna, Austria. Abstract LBA12.
  2. Diéras V, Miles D, Verma S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(6):732-742. doi: 10.1016/S1470-2045(17)30312-1.

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