First-line treatment with ado-trastuzumab emtansine (T-DM1) “provided a significant improvement” in progression-free survival when compared to trastuzumab (Herceptin) plus docetaxel in a randomized phase II study among patients with HER2-positive metastatic or recurrent locally advanced breast cancer. The median progression-free survival was 14.2 months with T-DM1 vs 9.2 months with the trastuzumab/docetaxel combination (hazard ratio = 0.59; 95% CI = 0.36–0.97), according to the study report published in the Journal of Clinical Oncology. T-DM1, an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab, also had a favorable safety profile compared to the trastuzumab/docetaxel combination, with fewer grade ≥ 3 adverse events (46.4% vs 90.9%).
“In this phase II, multicenter, open-label study, patients were randomly assigned 1:1 to either T-DM1 3.6 mg/kg intravenously (IV) once every 3 weeks or trastuzumab 8 mg/kg IV loading dose followed by 6 mg/kg once every 3 weeks and docetaxel 75 or 100 mg/m2 (per investigator discretion) IV once every 3 weeks,” with treatment continuing until progressive disease or unacceptable toxicity, the investigators explained.
“T-DM1 provided a clinically meaningful and statistically significant 41% reduction in the relative risk” of progressive disease compared with standard treatment, the researchers reported. The overall response rate was 58.0% (95% CI = 45.5%–69.2%) with three complete responses vs 64.2% (95% CI = 51.8%–74.8%) with seven complete responses in the TDM1 arm (P = .458).
The improvement in progression-free survival observed with T-DM1 “was associated with a more durable response, which could result from greater potency related to its unique mechanisms of action, longer treatment duration enabled by its favorable safety and tolerability, or both,” the authors wrote. Grade 4 adverse events were reported for 57.6% of patients receiving trastuzumab/docetaxel vs 5.8% of those receiving T-DM1. Adverse events leading to treatment discontinuation (of either drug) occurred in 40.9% of patients in the trastuzumab/docetaxel group vs 7.2% in the T-DM1 group, the investigators noted.
Due to study limitations, including the open-label design, immaturity of overall survival data, and large numbers of crossovers from the trastuzumab/docetaxel arm to the T-DM1 arm after disease progression, “these data should be considered hypothesis-generating, and they need to be validated by the results of MARIANNE,” the researchers stated. MARIANNE is an ongoing phase III randomized study of T-DM1 with or without pertuzumab (Perjeta) vs trastuzumab plus a taxane for the first-line treatment of HER2-positive metastatic breast cancer. ■
Hurvitz SA, et al: J Clin Oncol 31:1157-1163, 2013.