The New England journal of medicine 2012-11-08
Trastuzumab emtansine for HER2-positive advanced breast cancer.
Abstract
Background
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. The antibody and the cytotoxic agent are conjugated by means of a stable linker.
Methods
We randomly assigned patients with HER2-positive advanced breast cancer, who had previously been treated with trastuzumab and a taxane, to T-DM1 or lapatinib plus capecitabine. The primary end points were progression-free survival (as assessed by independent review), overall survival, and safety. Secondary end points included progression-free survival (investigator-assessed), the objective response rate, and the time to symptom progression. Two interim analyses of overall survival were conducted.
Results
Among 991 randomly assigned patients, median progression-free survival as assessed by independent review was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P<0.001), and median overall survival at the second interim analysis crossed the stopping boundary for efficacy (30.9 months vs. 25.1 months; hazard ratio for death from any cause, 0.68; 95% CI, 0.55 to 0.85; P<0.001). The objective response rate was higher with T-DM1 (43.6%, vs. 30.8% with lapatinib plus capecitabine; P<0.001); results for all additional secondary end points favored T-DM1. Rates of grade 3 or 4 adverse events were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia were higher with lapatinib plus capecitabine.
Conclusions
T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. (Funded by F. Hoffmann-La Roche/Genentech; EMILIA ClinicalTrials.gov number, NCT00829166.).
Related Questions
What second line treatment would you choose for a post menopausal woman with HR+ HER2+ metastatic breast cancer with low burden disease treated with first line aromatase inhibitor and trastuzumab?
The TAnDEM trial did prove that triple-positive metastatic breast cancer should be treated with both anti-HER2 therapy and endocrine therapy. Although there is no direct data in the setting of the above-described case to my knowledge, we can extrapolate from the large body of evidence that exists fo...
How do you approach a BRCA-mutated, premenopausal woman with metastatic ER+, Her2+ carcinoma with progression on THP?
This is probably not a common scenario, but one that theoretically crosses 3 areas of metastatic disease with largely non overlapping clinical trial data. It is somewhat unusual because premenopausal women with ER-positive/HER2 positive breast cancer have disease that is typically sensitive to estro...
When do you consider HER2-targeting antibody drug conjugates in the first line setting for metastatic HER2 positive, ER negative breast cancer?
This question cannot be answered for any specific situation with a high degree of reliability without a controlled clinical trial. In my opinion, there could be situations in which I would predict a favorable benefit/risk ratio to the use of T-DXd in first line as opposed to standard taxane + trastu...
Will you continue anti-estrogen therapy in the setting of initiation of TDM-1 for patients with metastatic ER+/HER2+ breast cancer?
The answer to this question has not been well studied, but the registration trials that led to the approval of T-DM1 (EMILIA and TH3RESA) did not use T-DM1 with concurrent hormonal therapy. Historically, we have avoided combining chemotherapy with hormonal therapy for breast cancer. This was in part...