Δευτέρα, 29 Μαΐου 2017

FINAL SURVIVAL ANALYSIS OF EMILIA AND THERESA

As reported in The Lancet Oncology by Diéras et al, the final overall survival results of the phase III EMILIA trial show improved outcome with ado-trastuzumab emtansine (Kadcyla) vs capecitabine plus lapatinib (Tykerb) in previously treated HER2-positive advanced breast cancer. Approval of trastuzumab emtansine for treatment of patients with HER2-positive metastatic breast cancer previously treated with trastuzumab (Herceptin) and a taxane is based on progression-free survival and interim overall survival findings in the trial.
Study Details
In the trial, 991 patients previously treated with trastuzumab and a taxane were randomized between February 2009 and October 2011 to receive ado-trastuzumab emtansine at 3.6 mg/kg every 3 weeks (n = 495) or oral capecitabine at 1,000 mg/m² twice daily on days 1 to 14 of each 21-day cycle plus lapatinib at 1,250 mg orally once daily on days 1 to 21 (n = 496). In May 2012, the study protocol was amended to allow crossover from control to ado-trastuzumab emtansine after the second interim overall survival analysis crossed the prespecified efficacy boundary.
Overall Survival
The cutoff date for the final analysis was in December 2014. The median duration of follow-up was 47.8 months in the ado-trastuzumab emtansine group and 41.9 months in the control group. Median overall survival was 29.9 months (95% confidence interval [CI] = 26.3–34.1 months) in the ado-trastuzumab emtansine group vs 25.9 months (95% CI = 22.7–28.3 months) in the control group (hazard ratio = 0.75, 95% CI = 0.64–0.88).
In the control group, 136 patients (27%) crossed over to ado-trastuzumab emtansine after the second interim overall survival analysis (median follow-up duration = 24.1 months). In the ado-trastuzumab emtansine group, 254 patients (51%) received capecitabine and 241 patients (49%) received lapatinib (separately or in combination) after ado-trastuzumab emtansine discontinuation. A post hoc sensitivity analysis that censored patients at the time of crossover to ado-trastuzumab emtansine showed similar outcome (median = 29.9 vs 24.6 months, HR = 0.69, 95% CI = 0.59–0.82).
Adverse Events
Grade ≥ 3 adverse events occurred in 48% of the ado-trastuzumab emtansine group vs 60% of the control group. The most common events were thrombocytopenia (14%), increased aspartate transaminase (5%), and anemia (4%) in the ado-trastuzumab emtansine group and diarrhea (21%), palmar-plantar erythrodysesthesia syndrome (18%), and vomiting (5%) in the control group. Three deaths in the ado-trastuzumab emtansine group (due to metabolic encephalopathy, neutropenic sepsis, and acute myeloid leukemia) and two deaths in the control group (due to coronary artery disease and multiorgan failure) were considered related to study treatment.
The investigators concluded: “This descriptive analysis of final overall survival in the EMILIA trial shows that trastuzumab emtansine improved overall survival in patients with previously treated HER2-positive metastatic breast cancer even in the presence of crossover treatment. The safety profile was similar to that reported in previous analyses, reaffirming trastuzumab emtansine as an efficacious and tolerable treatment in this patient population.”
The study was funded by F. Hoffmann-La Roche/Genentech.


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, = .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, = .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 Oncologyarticle. 

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