Ado-trastuzumab emtansine (formerly T-DM1; Kadcyla) improved overall survival compared with treatment of physician’s choice of therapy for patients with pretreated HER2-positive metastatic breast cancer, according to the phase III TH3RESA trial.¹ Patients enrolled in the trial had previously been treated with trastuzumab (Herceptin), taxane, and lapatinib (Tykerb).

Ado-trastuzumab emtansine achieved a clinically meaningful and statistically significant improvement in overall survival compared with treatment of physician’s choice of therapy (control arm, P = .0007)—a relative improvement of 32%. The absolute difference in survival in these patients who progressed on prior HER2-directed therapy was 6.9 months, with a median overall survival of 22.7 months for ado-trastuzumab emtansine vs 15.8 months for treatment of physician’s choice.

“This excellent survival benefit was achieved in the T-DM1 arm despite the facts that more than 50% of patients in the treatment of 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. These findings solidify the role of T-DM1 in patients with previously treated metastatic breast cancer,” stated lead author Hans Wildiers, MD, of the University Hospitals Leuven, Belgium, who presented the final overall survival results of this trial at the 2015 San Antonio Breast Cancer Symposium.

The antibody-drug conjugate ado-trastuzumab emtansine is approved by the U.S. Food and Drug Administration as a single agent for the treatment of HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane on the basis of the phase III EMILIA study, where it prolonged progression-free survival by about 3 months and overall survival by about 6 months.²

Study Details and Early Findings

“The TH3RESA trial evaluated the use of T-DM1 in a more advanced population than EMILIA,” he said. “TH3RESA randomized 602 patients to T-DM1 vs treatment of physician’s choice in a 2:1 ratio. When the EMILIA trial showed an overall survival benefit, patients in TH3RESA were allowed to cross over from treatment of physician’s choice to T-DM1 at disease progression,” explained Dr. Wildiers. 

At the first interim analysis of TH3RESA in 2013, progression-free survival was nearly doubled with ado-trastuzumab emtansine: 3.3 months with treatment of physician’s choice to 6.2 months with ado-trastuzumab emtansine. At that time, there were too few deaths to evaluate overall survival, but a trend in survival appeared to favor ado-trastuzumab emtansine.

Final Survival Results

At a median follow-up of 30.5 months, overall survival crossed the stopping boundary, said Dr. Wildiers. At baseline, ± 50% of patients had estrogen receptor–positive tumors, ± 75% had visceral involvement, more than 50% had received four or more prior regimens for advanced breast cancer, and about 10% of patients had previously treated brain metastases at baseline in the control arm and 67% in the ado-trastuzumab emtansine arm.

At the cutoff date, 79% of patients discontinued the study, the majority because of death. In the control arm, 45% of patients crossed over to ado-trastuzumab emtansine at disease progression within the study, and an additional 6% crossed over to ado-trastuzumab emtansine as a nonstudy treatment. “So at least 50% of patients on the treatment of physician’s choice of therapy arm got ado-trastuzumab emtansine at disease progression,” he said.

Regarding toxicity, grade 3 or higher nonhematologic toxicity was more frequent in the treatment of physician’s choice of therapy arm, and this was most pronounced for diarrhea. As for grade 3 or higher hematologic toxicity, neutropenia and febrile neutropenia were more frequent in the control arm, whereas thrombocytopenia was more frequent in the ado-trastuzumab emtansine arm. The incidence of grade 3 or higher adverse events was higher in the control arm: 47.3% compared with 40% in the ado-trastuzumab emtansine arm.

“As of data cutoff in February 2015, about 25% of patients in the trial were still being treated with ado-trastuzumab emtansine and had not yet progressed. There are some long-term survivors,” Dr. Wildiers said. ■

Disclosure: The study was supported by Roche. Dr. Wildiers’ institution has received funds from Roche for lectures and consulting work as well as an unrestricted grant for academic research.

References

1. Wildiers H, et al: 2015 San Antonio Breast Cancer Symposium. Abstract S5-05. Presented December 11, 2015.

2. Verma S, et al: N Engl J Med 367:1783-1791, 2012.