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 adverse events of grade 3 or above 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.)

Background: Evaluation of the long-term benefit of biologically-based regimens of trastuzumab in the early breast cancer population, and optimization of trastuzumab integration to maximize efficacy and minimize cardiac toxicity.Material and Methods: We randomized HER2-positive (FISH+) breast cancer patients with axillary lymph node positive or high risk negative, to either standard AC (60/600 mg/m2 q3wk x4) followed by T (100 mg/m2 q3wk x 4) or two trastuzumab-containing regimens; AC followed by T with trastuzumab x 1 year or TCarbo (75 mg/m2/AUC6 q3wk x 6) with trastuzumab x 1 year. Patients were prospectively stratified by number of positive nodes (0, 1-3 vs 4+) and hormone receptor status. Patients with ER and/or PR positive (HR+) tumors received hormone-directed therapy for 5 yrs after chemotherapy. The primary endpoint was disease-free survival (DFS) with 80% power (0.05 significance level) to detect an absolute difference of 7%. Secondary endpoints include overall survival (OS) and safety, including cardiac toxicity (symptomatic events and asymptomatic LVEF decline). The first two protocol-specified analyses for this study were performed at 300 and 450 disease-related events. We now report the results of the third protocol-specified analysis conducted after 650 events, expected by end of June 2009.Results: A total of 3222 patients (1072 in AC-T, 1076 in AC-TH and 1074 in TCH) were recruited between April 2001 and March 2004. Baseline characteristics of the study population will be included. Cox analysis of DFS and OS (unadjusted and adjusted for nodal status) and cardiac toxicity data will be presented for the three treatment arms.Discussion: The results of this trial help define the role of trastuzumab in the breast cancer HER2-positive adjuvant setting, as well as the risks/benefits of adjuvant trastuzumab within the context of overall safety including cardiac toxicity. This latter objective is of particular importance given that many of these women may be cured of their disease in the adjuvant setting. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 62.

Docetaxel was superior to paclitaxel in terms of OS and TTP. ORR was higher for docetaxel. Hematologic and nonhematologic toxicities occurred more frequently in the docetaxel group. The global quality-of-life scores were similar for both agents over time.

In this study,obesity was associated with poorer outcome in node-positive BC patients. Given the increasing prevalence of obesity worldwide, more research on improving the treatment of obese BC patients is needed.

Purpose: Targeting HER2 with multiple HER2-directed therapies represents a promising area of treatment for HER2-positive cancers. We investigated combining the HER2-directed antibody-drug conjugate trastuzumab emtansine (T-DM1) with the HER2 dimerization inhibitor pertuzumab (Perjeta).Experimental Design: Drug combination studies with T-DM1 and pertuzumab were performed on cultured tumor cells and in mouse xenograft models of HER2-amplified cancer. In patients with HER2-positive locally advanced or metastatic breast cancer (mBC), T-DM1 was dose-escalated with a fixed standard pertuzumab dose in a 3þ3 phase Ib/II study design.Results: Treatment of HER2-overexpressing tumor cells in vitro with T-DM1 plus pertuzumab resulted in synergistic inhibition of cell proliferation and induction of apoptotic cell death. The presence of the HER3 ligand, heregulin (NRG-1b), reduced the cytotoxic activity of T-DM1 in a subset of breast cancer lines; this effect was reversed by the addition of pertuzumab. Results from mouse xenograft models showed enhanced antitumor efficacy with T-DM1 and pertuzumab resulting from the unique antitumor activities of each agent. In patients with mBC previously treated with trastuzumab, lapatinib, and chemotherapy, T-DM1 could be dosed at the maximum tolerated dose (MTD; 3.6 mg/kg every 3 weeks) with standard dose pertuzumab. Adverse events were mostly grade 1 and 2, with indications of clinical activity.Conclusions: Dual targeting of HER2 with the combination of T-DM1 and pertuzumab in cell culture and mouse xenograft models resulted in enhanced antitumor activity. In patients, this combination showed an encouraging safety and tolerability profile with preliminary evidence of efficacy. Clin Cancer Res; 20(2); 456-68. Ó2013 AACR.