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.).

Figures

Figure 1. Progression-free Survival, as Assessed by an Independent Review Committee

Shown are Kaplan–Meier estimates of progression-free survival in the intention-to-treat population, stratified according to world region, number of prior chemotherapy regimens (0 or 1 vs. >1), and site of disease involvement (visceral vs. nonvisceral). Median progression-free survival was 3.2 months longer in the trastuzumab emtansine (T-DM1) group than in the lapatinib–capecitabine group. CI denotes confidence interval.

Figure 2. Second Interim Analysis of Overall Survival

Shown are Kaplan–Meier estimates of overall survival in the intention-to-treat population, stratified according to world region, number of prior chemotherapy regimens (0 or 1 vs. >1), and site of disease involvement (visceral vs. nonvisceral). The second interim analysis was conducted on the basis of 331 deaths and met the predefined O'Brien–Fleming stopping boundary. The data-cutoff date was July 31, 2012. Median follow-up was 18.6 months (range, 0 to 41) in the lapatinib–capecitabine group and 19.1 months (range, 0 to 40) in the T-DM1 group.