Expanding Treatment Options for HER2+ Breast Cancer - Episode 5
Adam Brufsky, MD, PhD: Before we get into the post-neoadjuvant setting, we’ll talk about the other big thing in this: what are we doing about the KAITLIN study? Does somebody want to talk about KAITLIN and those results? Mark, do you have that?
Mark D. Pegram, MD: Yes, I’ve got it. It was a substitution of T-DM1 [trastuzumab emtansine] for paclitaxel and 2 antibodies; it was T-DM1 plus pertuzumab. The trial did not meet its primary end point, so chemotherapy HP [trastuzumab, pertuzumab] remains the standard of care. Moreover, there were more dropouts in the T-DM1 arm, although the quality of life was a little bit better during the T-DM1 sequence in the trial. The bottom line is, it’s a negative study. It would be a consideration only for selected patients who can’t tolerate paclitaxel and 2 antibodies. For the vast majority of patients, it’s an interesting trial but didn’t meet its primary end point. It’s not superior, but it looks to be highly similar to the 2-antibody chemotherapy control. There would be no barrier to using it, in terms of efficacy, but really no advantage.
Adam Brufsky, MD, PhD: They made a big deal about how it was not noninferior, so they’re trying to tell you don’t use it. On the other hand, you’re going to have a woman who comes in who doesn’t want to lose her hair. What about then? That’s probably the only time I’d think about using this regimen. Virginia, what do you think?
Virginia Kaklamani, MD: You’re still using AC [doxorubicin, cyclophosphamide]….
Adam Brufsky, MD, PhD: I forgot, it’s true, you’re going to lose your hair. That doesn’t count.
Virginia Kaklamani, MD: This is not the only trial that has shown similar results with T-DM1 in the neoadjuvant setting compared to a taxane-based regimen. Then you look at the cost, and you realize it’s probably not worth it.
Adam Brufsky, MD, PhD: Especially now, we have biosimilars, so that’s a good point. Can anyone explain why that would be? I think it’s a really interesting scientific question. Shouldn’t it be better? It works as salvage therapy in the metastatic setting, but it’s not better in the first-line or frontline setting.
Mark D. Pegram, MD: That was shown last year by multiple trials that T-DM1 cannot accommodate HER2 heterogeneity. In the Dana-Farber Cancer Institute study, about 10% of their patients were heterogeneous and they had a lower PCR [pathologic complete response] rate to T-DM1. The same was true in the neoadjuvant trial, also about the same frequency. About 10% or so didn’t respond from the get-go during the T-DM1 neoadjuvant treatment. I-SPY 2 also showed similar results that T-DM1, as a single agent since it lacks a bystander effect, T-DM1 is not soluble, it can’t diffuse into adjacent tumor cells after dead cells are lysed. That’s a big handicap of T-DM1.
Adam Brufsky, MD, PhD: That point is an excellent one. The fact that you need functional HER2 expression to have it, and if you don’t, or there’s not enough amplification, it’s not going to work. That’s an important clinical pearl. As you know from San Antonio Breast Cancer Symposium, the whole ATEMPT trial, comparing T-DM1 to TH [paclitaxel, trastuzumab], you’re ready to reach for the T-DM1, but the woman has heterogeneous disease. I never would have thought of that. Does anyone want to comment on that?
Mark D. Pegram, MD: The other issue is a dose. T-DM1 maintains all of the attributes of trastuzumab, the naked antibody, insofar as it has signal perturbation, in terms of HER2/HER3 association, it engages activating Fc gamma receptors in NK [natural killer] cells. If any of those are also important to the mechanism of trastuzumab with chemotherapy, you probably lose some of that with T-DM1 because of the much lower dose, almost half, and the half-life is far shorter with T-DM1 compared to free antibody. That’s another mechanism of potential failure.
Adam Brufsky, MD, PhD: The dose is 3.6mg per kg? And every 3 weeks?
Mark D. Pegram, MD: The half-life is less than a week. The trastuzumab half-life is 3 to 4 weeks.
Adam Brufsky, MD, PhD: I never thought of that, either. These are very good points.
Virginia Kaklamani, MD: When you look at the presentation that they did, it seems that they presented data at ESMO Breast, about the patients who, post-neoadjuvantly, were HER2 negative, and these patients did get benefit from T-DM1. How is that explained?
Adam Brufsky, MD, PhD: Let’s answer it. I don’t know the answer. Mark, what do you think?
Mark D. Pegram, MD: I don’t think that in the case of T-DM1 the question of HER2-low has been critically addressed. There’s been a small study but in that study, HER2-low included 1-plus and 2-plus. The current IHC [immunohistochemistry] antibodies that are commercially available for HER2 testing were not designed to discriminate the nuances below 3-plus. I can envision, especially in the case of micrometastasis, there may be some cells that have just enough HER2. All you need to get is internalization and then DM1 can nicely kill the tumor cells. You have to have enough, though, and these heterogeneous cases seem to be admixtures of truly HER2 negative cells mixed with HER2 positives. Those are the ones in which T-DM1 seems to fail, in the neoadjuvant setting.
Adam Brufsky, MD, PhD:These are all excellent points.
Transcript Edited for Clarity