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

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.