Expanding Treatment Options for HER2+ Breast Cancer - Episode 6

HER2+ Early Stage Breast Cancer With Residual Invasive Disease

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Adam Brufsky, MD, PhD: Let’s go to the post-neoadjuvant setting. Rashmi, does everybody get T-DM1 [trastuzumab emtansine] post-neoadjuvantly right now at The University of Texas MD Anderson Cancer Center who has residual disease after TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] or whatever you give them?

Rashmi K. Murthy, MD, MBE: Anybody with residual disease we offer T-DM1 to. One piece of the striking data from the KATHERINE study that hit home for me is the impact of T-DM1 versus Herceptin on the patients who develop CNS [central nervous system] metastasis, there really wasn’t a huge difference. There was about 5% in both arms who still ended up with CNS relapse. Thinking about the role for a drug such as neratinib, a HER2 tyrosine kinase inhibitor, in the extended adjuvant setting, after T-DM1, even though we don’t have data for that, we don’t have data for the role of neratinib, pertuzumab, or T-DM1, given that patient population that is not receiving much benefit or impact from T-DM1. There should be some thought for use of neratinib. I certainly discuss it with my patients who are extremely motivated, who are younger, and who have very high-risk residual disease. If they have a large amount of residual disease after neoadjuvant therapy, I do talk about both T-DM1 as well as extended therapy with neratinib.

Adam Brufsky, MD, PhD: Before we get into the lower limit of what people would treat with here, let me ask a question. Are you involved in the COMPASS trial now? I know you were involved in HER2CLIMB? Are you involved in COMPASS at all?

Rashmi K. Murthy, MD, MBE: I am involved in COMPASS, so that’s another trial that’s coming up that patients will be able to enroll onto. It is going through the regulatory process.

Adam Brufsky, MD, PhD: Can you explain that design to our viewers because it’s a really cool trial that is going to be very important?

Rashmi K. Murthy, MD, MBE: This is a randomized study that is looking at patients with residual disease after neoadjuvant treatment with a taxane plus dual HER2-targeting with trastuzumab and pertuzumab. It randomizes patients in the postoperative setting to receive either T-DM1 or T-DM1 plus tucatinib. The thought is to further escalate adjuvant therapy for those with residual disease.

Adam Brufsky, MD, PhD: That’s cool. We’re going to trials because it was a 12% relapse rate despite the T-DM1, 11%, 12%, and half of that was brain metastases. The brain metastases, as you pointed out, are going to become the most important thing. Obviously, resistance is important, but clearly, we have a wide-open field to be able to treat that 5% or 6% of people who develop brain metastases as a first sign of relapse. Let me ask Carey. What’s the minimum amount of disease you would treat in the post-neoadjuvant with this therapy?

Carey K. Anders, MD: I remember right after KATHERINE was presented, I got an email from a colleague, I’d just gone home after the San Antonio Breast Cancer Symposium conference, and said, “I had a patient who just came in after her TCHP. She has 8 mm residual disease, lymph node negative, would you give T-DM1?” I went back to the paper in The New England Journal of Medicine, and if you look at the forest plots, pretty much every stage of residual disease benefited from the T-DM1 over trastuzumab. I really haven’t had a lower limit cutoff. I’d be curious to hear if others have taken a different approach, but I’ve routinely recommended T-DM1 and I’m happy to have the COMPASS study on the horizon with the addition of the tyrosine kinase inhibitor to see if that might help, as well.

The other thing I think is perplexing, and I see this a lot in my practice taking care of patients with brain metastasis, is I also see patients with pathologic complete response [path CR] recur in the brain as the only site of disease. It’s something for us to think about for our patients who have a path CR. It would be nice to have some predictor, even in those patients we relax our shoulders about, to know if they are at higher risk for CNS recurrence.

I think as much as we congratulate the path CR, I am struck by the number of women I see in my CNS metastasis clinic who had a path CR to HER2-directed therapy. I just want us to think about that further.

Adam Brufsky, MD, PhD: I agree. Mark, do you think the prevention of brain metastases in this setting is going to be an advance if we can do it?

Mark D. Pegram, MD: It would be huge, there’s no doubt about it. I do like the idea of integrating tucatinib into the extended adjuvant setting because as a single agent, and certainly in combination with endocrine therapy, it would be very manageable in terms of safety signals. In addition to combining it with T-DM1, one wonders, could you do it following T-DM1 and perhaps even as a primary end point of onset to brain metastasis? I think that would be a very clever strategy moving forward.

Adam Brufsky, MD, PhD: The problem is that the power of this is going to be huge. What is COMPASS going to be, a couple thousand patients? We are getting to the point now where we’re above 90%, and to get each little increment above that is going to take thousands of people. Like the cardiologists, I don’t know what we’re going to do. I don’t know where we are going to find all these people. It’s going to be really tough.

Transcript Edited for Clarity