Survival Benefit for T-DM1 Confirmed in Metastatic Breast Cancer

April 2016, Vol 7, No 3

The antibody-drug conjugate trastuzumab emtansine (T-DM1) improved overall survival (OS) compared with physician’s choice of therapy in patients with pretreated HER2-positive metastatic breast cancer, according to the final results of the phase 3 TH3RESA trial, which were presented at the 2015 San Antonio Breast Cancer Symposium.

Treatment with T-DM1 led to a clinically meaningful and statistically significant improvement in OS compared with physician’s choice of therapy (control arm, P = .0007), reflecting a relative improvement of 32%. The absolute difference in survival in these patients who progressed with previous HER2-­directed therapy (trastuzumab, taxane, and lapatinib) was 6.9 months, with a median OS of 22.7 months with T-DM1 versus 15.8 months with physician’s choice of therapy.

“This excellent survival benefit was achieved in the T-DM1 arm despite the fact that more than 50% of patients in the physician’s choice of therapy arm crossed over to T-DM1, and about 80% of patients in the control arm had received trastuzumab-containing regimens,” stated lead investigator Hans Wildiers, MD, PhD, University Hospitals Leuven, Belgium. “These findings solidify the role of T-DM1 in patients with previously treated metastatic breast cancer.”

Survival Benefit with T-DM1

The TH3RESA trial included 602 patients who were randomized to T-DM1 or to physician’s choice of therapy, and who were allowed to cross over to T-DM1 at disease progression, Dr Wildiers explained.

At the first interim analysis of TH3RESA, T-DM1 doubled progression-free survival to 6.2 months from 3.1 months with physician’s choice of therapy. At that time, a trend toward improved survival was seen for T-DM1, but it was too early to evaluate OS.

The final analysis of OS showed that, at a median follow-up of 30.5 months, OS crossed the stopping boundary.

At baseline, the patients in the trial were very sick, with 50% having estrogen receptor–positive tumors, 75% with visceral involvement, >50% with brain metastases, and approximately 10% of patients had to be stabilized before initiating the study treatment.

Within the study, 49% of the control arm crossed over to T-DM1 at disease progression, and another 6% of patients crossed over as a nonstudy treatment. The patients received treatment until disease progression.

Nonhematologic toxicity was reported more frequently with physician’s choice of therapy, with more diarrhea, neutropenia, and febrile neutropenia. Thrombocytopenia was more frequent in the T-DM1 arm. The incidence of grade ≥3 adverse events was higher in the control arm (47.3%) compared with the T-DM1 arm (40%).

As of the data cutoff in February 2015, approximately 25% of the patients in the trial were still receiving T-DM1 and had not yet progressed. “There are some long-term survivors,” Dr Wildiers noted.


C. Kent Osborne, MD, Director, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, and moderator of the press conference where these data were presented, said that now that there is a biomarker for the treatment of patients with HER2-positive breast cancer, and there are treatments targeted to this biomarker, “It turns out that HER2-positive breast cancer is a good tumor to have.”

“This study raises an interesting question of how long to keep patients on the drug if they are in complete remission,” Dr Osborne continued. “This also raises the issue of cost and the question of who to treat. Luckily, the biomarker shows us who to treat.”

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