Final Overall Survival Results of TH3RESA Trial in Breast Cancer
The final overall survival results of the phase III TH3RESA trial indicate a 32% reduction in risk of death with ado-trastuzumab emtansine (Kadcyla) vs treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer. The findings were reported in The Lancet Oncology by Krop et al.
Study Details
In the trial, 602 patients previously treated with both trastuzumab (Herceptin) and lapatinib (Tykerb; advanced setting) and a taxane (any setting) and with disease progression on at least 2 HER2-directed regimens in the advanced setting were randomized 2:1 between September 2011 and November 2012 to receive ado-trastuzumab emtansine at 3.6 mg/kg every 21 days (n = 404) or treatment of physician’s choice (n = 198). Of 185 patients in the physician’s choice group who received study treatment, 153 received combination therapy including a HER2-directed agent.
In September 2012, the study protocol was amended to allow patients in the physician’s choice group to cross over to ado-trastuzumab emtansine at disease progression. As reported previously, ado-trastuzumab emtansine was associated with a significantly prolonged progression-free survival, a co-primary endpoint along with overall survival. The current report is from the second interim analysis of overall survival, which was planned to occur when approximately 67% (n = 330) of 492 expected deaths had occurred.
Improved Overall Survival
As of data cutoff in February 2015, 47% of the physician’s choice group had crossed over to ado-trastuzumab emtansine. Median follow-up was 30.5 months. At the interim analysis, median overall survival was 22.7 months (95% confidence interval [CI] = 19.4–27.5 months) in the ado-trastuzumab emtansine group vs 15.8 months (95% CI = 13.5–18.7 months) in the physician’s choice group (hazard ratio [HR] = 0.68, P = .0007). The stopping boundary for overall survival was crossed, making this analysis the final analysis and resulting in study termination.
A post-hoc sensitivity analysis that censored patients at the time of crossover to ado-trastuzumab emtansine showed consistent results (median = 22.7 months vs 15.6 months, HR = 0.58, P = .0002). Subgroup analyses showed consistent benefits of ado-trastuzumab emtansine according to age, number of previous treatment regimens, visceral disease involvement, tumor hormone receptor status, presence or absence of brain metastases, and type of treatment of physician’s choice.
Adverse Events
Grade ≥ 3 adverse events occurred in 40% of the ado-trastuzumab emtansine group vs 47% of the physician’s choice group. Those events that were ≥ 3% more common in the ado-trastuzumab emtansine group consisted of thrombocytopenia (6% vs 3%) and hemorrhage of any type (4% vs < 1%). Serious adverse events occurred in 25% vs 22%. Death due to adverse events occurred in nine patients (2%; three related to treatment) and three patients (2%; one related to treatment), respectively.
The investigators concluded: “In patients who had progressed on two or more HER2-directed regimens, trastuzumab emtansine treatment resulted in a significant improvement in overall survival versus treatment of physician’s choice. These data further solidify the role of trastuzumab emtansine in the management of patients with previously treated HER2-positive advanced breast cancer and validate HER2 as a therapeutic target even after multiple lines of previous therapy.”
The study was funded by F. Hoffmann-La Roche/Genentech.
Ian E. Krop, MD, of the Dana-Farber Cancer Institute, is the corresponding author of The Lancet Oncology article.
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®.
