Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2) -positive breast cancer after prior HER2-directed therapy

Howard A. Burris, Hope S. Rugo, Svetislava J. Vukelja, Charles L. Vogel, Rachel A. Borson, Steven Limentani, Elizabeth Tan-Chiu, Ian E. Krop, Richard A. Michaelson, Sandhya Girish, Lukas Amler, Maoxia Zheng, Yu Waye Chu, Barbara Klencke, Joyce A. O'Shaughnessy

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Abstract

Purpose: The antibody-drug conjugate trastuzumab-DM1 (T-DM1) combines the biologic activity of trastuzumab with targeted delivery of a potent antimicrotubule agent, DM1, to human epidermal growth factor receptor 2 (HER2) -overexpressing cancer cells. Based on results from a phase I study that showed T-DM1 was well tolerated at the maximum-tolerated dose of 3.6 mg/kg every 3 weeks, with evidence of efficacy, in patients with HER2-positive metastatic breast cancer (MBC) who were previously treated with trastuzumab, we conducted a phase II study to further define the safety and efficacy of T-DM1 in this patient population. Patients and Methods: This report describes a single-arm phase II study (TDM4258g) that assessed efficacy and safety of intravenous T-DM1 (3.6 mg/kg every 3 weeks) in patients with HER2-positive MBC who had tumor progression after prior treatment with HER2-directed therapy and who had received prior chemotherapy. Results: With a follow-up of ≥ 12 months among 112 treated patients, the objective response rate by independent assessment was 25.9% (95% CI, 18.4% to 34.4%). Median duration of response was not reached as a result of insufficient events (lower limit of 95% CI, 6.2 months), and median progression-free survival time was 4.6 months (95% CI, 3.9 to 8.6 months). The response rates were higher among patients with confirmed HER2-positive tumors (immunohistochemistry 3+ or fluorescent in situ hybridization positive) by retrospective central testing (n=74). Higher response rates were also observed in patients whose tumors expressed ≥ median HER2 levels by quantitative reverse transcriptase polymerase chain reaction for HER2 expression, compared with patients who had less than median HER2 levels. T-DM1 was well tolerated with no dose-limiting cardiotoxicity. Most adverse events (AEs) were grade 1 or 2; the most frequent grade ≥ 3 AEs were hypokalemia (8.9%), thrombocytopenia (8.0%), and fatigue (4.5%). Conclusion: T-DM1 has robust single-agent activity in patients with heavily pretreated, HER2-positive MBC and is well tolerated at the recommended phase II dose.

Original languageEnglish (US)
Pages (from-to)398-405
Number of pages8
JournalJournal of Clinical Oncology
Volume29
Issue number4
DOIs
StatePublished - Feb 1 2011
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Burris, H. A., Rugo, H. S., Vukelja, S. J., Vogel, C. L., Borson, R. A., Limentani, S., Tan-Chiu, E., Krop, I. E., Michaelson, R. A., Girish, S., Amler, L., Zheng, M., Chu, Y. W., Klencke, B., & O'Shaughnessy, J. A. (2011). Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2) -positive breast cancer after prior HER2-directed therapy. Journal of Clinical Oncology, 29(4), 398-405. https://doi.org/10.1200/JCO.2010.29.5865