5MJC BCU 3: Phase II Study of Trastuzumab-DM1 (T-DM1) for Patients with Previously Treated HER2-Positive Metastatic Breast Cancer

Phase II Study of Trastuzumab-DM1 (T-DM1) for Patients with Previously Treated HER2-Positive Metastatic Breast Cancer

Slides from a poster at SABCS 2009 and transcribed comments from an interview with Mark D Pegram, MD (12/23/09)

Presentation discussed in this issue:

Krop I et al. A Phase II study of trastuzumab-DM1 (T-DM1), a novel HER2 antibody-drug conjugate, in patients previously treated with lapatinib, trastuzumab, and chemotherapy. SABCS 2009;Abstract 5090.

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DR PEGRAM: Trastuzumab-DM1 (T-DM1) is an immunoconjugate with trastuzumab as the backbone. The idea is to use trastuzumab as a vehicle to deliver a microtubule-interacting poison, maytansine, which as a single agent is too toxic to be given to humans via IV. But when it’s coupled to trastuzumab, it’s really a potent cytotoxic against HER2-positive tumor target cells.

I found amazing the high degree to which the patient population had been pretreated in this study. Given such a heavily pretreated patient population, you might expect that there would be no efficacy signal for a new targeted agent in that setting. But single-agent T-DM1 demonstrated a response rate of 39.5 percent in that patient population with HER2-positive disease.

I think that it is stunning to have a patient population treated previously with lapatinib, trastuzumab and chemotherapy and to still retain an efficacy signal greater than a third. There have been previous papers showing that T-DM1 really requires HER2 overexpression for activity. There should be a low expectation for collateral damage to other normal tissues that lack HER2 overexpression compared to the HER2-positive tumor targets. Also T-DM1 does not cause alopecia, neutropenia or extensive nausea/vomiting. This begs the question in my mind: Can T-DM1 replace chemotherapy in combination with trastuzumab? I think that’s an extremely intriguing question and one that absolutely merits the attention of clinical trialists and the cooperative groups.

DR LOVE: Are there trials up and running that are looking at T-DM1 versus chemotherapy/trastuzumab?

DR PEGRAM: The current ongoing registration trial is a Phase III trial of T-DM1 as a single agent versus capecitabine with lapatinib in a patient population that would be suitable for capecitabine with lapatinib treatment. If that study is positive, then the next move that I would like to see would be a head-on comparison of T-DM1 versus trastuzumab/chemotherapy. I’ve seen a Phase II study underway evaluating the efficacy and safety of taxane/trastuzumab versus T-DM1 in patients who have not received prior chemotherapy for metastatic disease. Neoadjuvant trials looking at T-DM1 head on against chemotherapy/trastuzumab would also be an ideal study design to critically interrogate its capabilities.

DR LOVE: Do you think we’re moving fast enough in studying T-DM1?

DR PEGRAM: The process of meeting the regulatory requirements, though necessary, is painstaking and slow. When you see something this potent, your immediate instinct is to want to move it forward as quickly as possible. I think it is being moved forward as quickly as possible — the registration trial is already underway. Once it gets a label indication, it will allow for numerous investigator-initiated trials and will automatically spark an interest on the part of the cooperative groups to do adjuvant studies.

Dr Pegram is Full Professor of Medicine and Director for the Translational Research Program at the UM Sylvester Comprehensive Cancer Center’s Braman Family Breast Cancer Research Institute in Miami, Florida.




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The annual San Antonio Breast Cancer Symposium (SABCS) is unmatched in its significance with regard to the advancement of breast cancer treatment. It is targeted by many members of the clinical research community as the optimal forum in which to unveil new clinical data. This creates an environment each year where published results from a plethora of ongoing clinical trials lead to the emergence of many new therapeutic agents and changes in the indications for existing treatments across all breast cancer subtypes. In order to offer optimal patient care — including the option of clinical trial participation — the practicing medical oncologist must be well informed of the rapidly evolving data sets in breast cancer. To bridge the gap between research and patient care, this CME activity will deliver a serial review of the most important emerging data sets from the latest SABCS meeting, including expert perspectives on how these new evidence-based concepts can be applied to routine clinical care. This activity will assist medical oncologists and other cancer clinicians in the formulation of optimal clinical management strategies for breast cancer.


  • Assess the efficacy of the anti-HER2 agent T-DM1 in the treatment of patients with HER2-positive metastatic breast cancer who have experienced disease progression on chemotherapy and anti-HER2 therapy.

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Mark D Pegram, MD
Full Professor of Medicine
Director for the Translational Research Program
Braman Family Breast Cancer Research Institute
UM Sylvester Comprehensive Cancer Center
Miami, Florida

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Last review date: January 2010
Expiration date: January 2011