DR HURVITZ: The EMILIA study is a 990-or-so-patient clinical trial — HER2-positive, metastatic breast cancer that had been pretreated with trastuzumab — comparing T-DM1 to lapatinib and capecitabine, which is standard of care after trastuzumab. This study showed, at ASCO, a significant 3-month improvement in progression-free survival and subsequently, at the second interim overall survival analysis, also showed a significant improvement in overall survival. The delta was about 6 months and met their prespecified crossing boundary p-value. That was published in the New England Journal of Medicine.
T-DM1 not only has impressive data in terms of efficacy, but very little toxicity. The majority of women don’t lose their hair. They feel well on it and they’re able to live their life. Truly, there’s an ability to strike the balance between quality of life and quantity of life with this drug.
DR LOVE: Hope, where does T-DM1 fit in now?
DR RUGO: We participated in the 2 Phase II trials, and we had 3 patients who stayed on it for 3 1/2 years. There is that sort of subset of patients, by no means the majority, who stay on for a really long time and tolerate it well.
What happens to them afterwards still, I think, remains to be seen. There are a lot of patients for whom losing their hair is a really, really big issue in the metastatic setting. So I think I would feel comfortable using T-DM1 as a first-line approach, particularly because there was such a significant survival advantage compared to lapatinib and capecitabine, as Sara just discussed.
Then, of course, whatever line after that would be fine as well. I’m also very interested in the data that we’ll see in combination with pertuzumab from the MARIANNE trial and also the adjuvant studies, which are going to start up — a trial in very small HER2-positive disease and a trial in older patients with bigger disease, both out of Dana-Farber.
DR LOVE: Any situations outside a protocol setting, if you could do it, where you’d give T-DM1 plus pertuzumab?
DR RUGO: I think that we’re going to see the MARIANNE data before we need to make that decision. And I know that sounds like a hedge, but I probably would not combine them until I saw some information about the effects.
DR LOVE: Edith?
DR PEREZ: T-DM1, I think it builds on the whole idea that we’ve had targeted therapy. Let’s give the chemotherapy to the cells that actually overexpress HER2.
In terms of use, we’ve been very fortunate to have many trials available over the years. But in terms of what’s happening with the first-line setting, actually Sara and I worked on a randomized Phase II study, and it’s in press. Sara will be the first author on the paper coming out in JCO, documenting the activity of T-DM1 in the first-line setting versus docetaxel/trastuzumab — I think very exciting data for everyone to see.
DR LOVE: Adam?
DR BRUFSKY: Basically, first line is going to be a THP or something like it. Second line will be T-DM1 until MARIANNE comes out. Then for patients who are progressing right now beyond the second line, when TDM becomes available, you can give it.
DR LOVE: Sara?
DR HURVITZ: I agree with what Adam said — currently, THP first line. And I would use T-DM1 beyond the first-line setting. In the adjuvant and neoadjuvant setting, I would not use it outside of a trial at this point.
DR LOVE: Have we learned anything more in terms of the thrombocytopenia?
DR HURVITZ: The thrombocytopenia occurs anywhere — 25% to 30% of patients — all grade, can be severe in around 10% of patients. Still, the mechanism of action is unknown. There was a pharmacokinetic, pharmacodynamic semimechanistic modeling that was done, a paper that was released just recently. Essentially what they did was use data from the Phase I and one of the Phase II studies in order to understand how platelet levels changed over time in patients on these studies. They validated their model using the second Phase II study and showed that the first decrease in platelets that occurs is the greatest. There’s an acute drop around day 8 of cycle 1 of the first cycle. Then it becomes less severe later. But then there’s this second thing, which is platelet drift over subsequent cycles, that gradually patients have lower and lower platelets. But around cycle 8, that drift stops. It may be because the T-DM1 is no longer targeting a pool of platelets that is sensitive to this effect.