ECC 2013: Strong Showing for Ado-Trastuzumab Emtansine in Heavily Pretreated Advanced HER2-Positive Breast Cancer


Key Points

  • The phase III TH3RESA trial affirms the results of the earlier EMILIA study, demonstrating a consistent progression-free survival benefit of ado-trastuzumab in previously treated HER2-positive advanced breast cancer.
  • Patients in the ado-trastuzumab emtansine group had a median progression-free survival of 6.2 months vs 3.3 months in the control arm.
  • Median overall survival has not yet been reached in the ado-trastuzumab emtansine arm.

Results of the phase III TH3RESA trial show that the antibody-conjugate ado-trastuzumab (Kadcyla, previously known as T-DM1) extends progression-free survival in women with advanced HER2-positive breast cancer that progressed on two or more previous HER2-directed therapies including trastuzumab (Herceptin) and lapatinib (Tykerb). The findings were presented at the European Cancer Congress 2013 (Abstract 15) in Amsterdam.

These results build on those of the EMILIA trial, which showed that ado-trastuzumab emtansine extended progression-free survival compared with capecitabine/lapatinib in HER2-positive advanced breast cancer in women previously treated with trastuzumab and a taxane.

“In TH3RESA, [ado-trastuzumab emtansine] demonstrated improved safety and efficacy compared with the physician’s choice of chemotherapy. [Ado-trastuzumab emtansine] achieved a significant improvement in progression-free survival, and the effect was clear and consistent across subgroups. These data affirm the results of EMILIA, demonstrating a consistent progression-free survival benefit of [ado-trastuzumab emtansine] in patients with previously treated HER2-positive advanced breast cancer,” said Hans Wildiers, MD, PhD, of University Hospitals Leuven in Leuven, Belgium, the author of the late-breaking presentation. Dr. Wildiers added that ado-trastuzumab emtansine should become the new standard of care for second-line treatment.

Ado-trastuzumab emtansine is an antibody-drug conjugate currently FDA-approved for metastatic breast cancer previously treated with a taxane and trastuzumab.


The study included 602 patients with advanced breast cancer previously treated with at least two previous HER2-directed therapies. Patients were randomly assigned in a 2:1 ratio to ado-trastuzumab emtansine or physician’s choice of chemotherapy (83% received trastuzumab-based regimens and 17% received chemotherapy). Treatment was continued until disease progression, at which point patients were allowed to crossover to ado-trastuzumab emtansine.

Patients in the ado-trastuzumab emtansine group had a median progression-free survival of 6.2 months—nearly double that of the patients in the control arm (3.3 months). This was a highly significant difference in favor of ado-trastuzumab emtansine (P < .001). A prespecified subgroup analysis showed a consistent, near-doubling of progression-free survival with ado-trastuzumab emtansine regardless of subgroup (age, geographic area, race, performance status, tumor characteristics, and visceral disease).

The first interim analysis of overall survival showed median survival of 14.9 months in the control arm; median overall survival was not yet reached in the ado-trastuzumab emtansine arm at the time of analysis. Although this suggests that there may be a survival advantage for ado-trastuzumab emtansine, long-term confirmation is needed. Final survival results are expected in 2015.

Safety Profile Consistent With Prior Studies

The safety of ado-trastuzumab emtansine was reassuring and similar to what was reported in the EMILIA trial. Adverse events of grade 3 or higher were more frequent in the control arm: 43.5% vs 32.3% in the ado-trastuzumab emtansine arm. Adverse events of any grade were reported by 94% for those who received ado-trastuzumab emtansine vs 89% for the control arm. Adverse events leading to discontinuation of therapy occurred in 10.9% of controls vs 6.7% of the ado-trastuzumab emtansine group. The rate of cardiac events was low in both arms: Left-ventricular ejection fraction < 50% was reported in 1.1% and 1.5%, respectively.

According to Dr. Wildiers, an ongoing phase III trial is evaluating use of ado-trastuzumab emtansine as first-line therapy in advanced HER2-positive breast cancer, and results are expected next year. The benefit of treating with ado-trastuzumab emtansine after disease progression will also be studied.

Formal discussant Clifford Hudis, MD, ASCO President and Chief of Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center in New York, commented that the results were not surprising. “The results of TH3RESA nicely reflect the EMILIA trial and are consistent with those of anti-HER2 therapies. These antibody-based therapies have revolutionized the treatment of a subset of breast cancer patients.”

Remaining issues are the optimal sequencing of HER2-directed therapies and the best role for ado-trastuzumab emtansine, he said.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.