Individualized Treatment Decisions for HER2+ Breast Cancer

Lisa A. Carey, MD, FASCO: Let’s talk a bit about this theme of individualized therapy and how you select patients. We’ve got an embarrassment of riches, which we talked about earlier. How do you toggle between safety, efficacy, existing trial data, and populations as you’re trying to put these things into context of your own practice? Let’s talk about tucatinib, CAPE [capecitabine], and trastuzumab. As Lee said, I think most of us in the first-line would use THP [docetaxel, trastuzumab and pertuzumab] or ETHP [etoposide, docetaxel, trastuzumab, pertuzumab], or something with H and P [trastuzumab and pertuzumab] involved; T-DM1 [trastuzumab emtansine] in the second-line; and typically tucatinib, capecitabine, trastuzumab in the third-line. But do you start to think about these therapies differently in patients with active brain mets [metastases]? Do you think differently in patients with lots of disease? We now have trastuzumab deruxtecan, which is wildly active, in at least a single-arm study, but with 6 prior therapies, you have to take it seriously. Do you use volume of disease, nature, hormone receptor, and CNS [central nervous system] involvement? Do you handle these things differently? It’s a general poll question because we will talk specifically about the brain and hormone receptor-positive, HER2-positive disease in a second.

Vijayakrishna Gadi, MD, PhD: I’ll start on this one. I think what we’re coming down to is the third-line and beyond, so the HER2CLIMB, the deruxtecan, etc, because in those first 2 lines, we have pretty solid, mature data with OS [overall survival] benefits, and it’s harder to dispute the value of those. There might be a patient with a brain metastasis or what have you, where you want to use one of the other agents. But in general, I think many of us would stick with those.

It’s funny how everybody is excited about deruxtecan, I am as well; it’s a very active drug. The waterfall plot has a 98% DCR [disease control rate], and that’s pretty good. But when you look at the same waterfall plot from the tucatinib arm in the HER2CLIMB study, it has a 92% DCR. That isn’t bad. We always ask, “What are the data we want to see from a trial?” We want to see not only the PFS [progression-free survival], but the OS in a randomized, controlled, carefully done study. We have that with tucatinib. For me, it takes a lot to bump tucatinib off and consider something else, because it works in patients with visceral disease, with brain metastases, etc, and has the highest level of data evidence. That’s what we’re supposed to help guide us, right? That’s why I generally favor that regimen more so than the deruxtecan, but there may be a patient where that might not be the right answer and I understand that. But in general, that’s the way I’m going to approach it.

Lisa A. Carey, MD, FASCO: Alright, let me challenge you on one thing. I’ll skip ahead. If a patient has active brain metastases after locally directed therapy, do you bump it up to the second-line?

Vijayakrishna Gadi, MD, PhD: Yes, I think we could consider bumping it up to the second-line in that kind of patient, but it will depend on the volume of the disease and the recency of the brain metastases. If it’s two 1-cm lesions that I can get with SRS [stereotactic radiosurgery], I might be tempted to keep the patient on the T-DM1 [trastuzumab emtansine] in that setting. But if I’m getting the sense of a tempo that’s different, and I think I’m going to need that control in a different way, I’m going to look at tucatinib earlier.

Lisa A. Carey, MD, FASCO: Yes, it’s hard. The EMILIA subsets, other trastuzumab emtansine trials, the KAMILLA trial, the subset with brain metastases did as well as the subset without brain metastases. The problem is, of course, all these studies, as I think Lee said earlier, didn’t allow active brain metastases. The HER2CLIMBtrial was the first to take a swing at that particular thing. Anybody else?

Lee S. Schwartzberg, MD, FACP: I would say that in the adjuvant setting, again with increasing use of trastuzumab emtansine, which almost all my patients are getting, except for the very small lesions, and even T1c tumors may be getting neoadjuvant now because our surgeons like to operate on smaller lesions. So many patients are getting exposed to, roughly half who don’t achieve a pCR [pathologic complete response], to trastuzumab emtansine. Then the tempo of relapse is important, and the time on first-line therapy also. For someone who had a PFS less than the median, or substantially less than the median of CLEOPATRA, with an HP [trastuzumab, pertuzumab] and taxane regimen, I might consider jumping to second-line tucatinib as a different alternative and using a TKI [tyrosine kinase inhibitor]. So, it’s all those features. I think like everyone has said, treatment is about a patient-centered approach and it’s very specific now. Because we have these options, we can integrate toxicity, prior therapy, and disease burden into our decision-making.

Reshma Mahtani, DO: The only thing I’ll add is, obviously, I take all of these factors that we’ve brought up into account, in terms of disease burden, patient preference, and CNS vs systemic disease. But I think as we look at how to sequence these therapies, something that gets forgotten is that all of us are starting to get a different feeling regarding HER2+ disease in general, because we have all of these active agents. But every once in a while, you are faced with that recollection that this is an aggressive subset of breast cancer. As we look at how are we going to use these therapies, we have the thought, “Well, we have these new drugs, and everybody is going to get exposed to them at some point. The sequencing may not matter as much.” But some patients don’t make it to third- or fourth-line therapy. As you have that decision in front of you, with a patient who is very symptomatic and has a huge burden of visceral disease, you’re faced with the decision of what is my agent with the highest activity to get them feeling better? Of course, a survival benefit, as V.K. pointed out, is very important, but I think that also brings up the importance of a response rate and an agent that has a quick response because you may not get the opportunity to get to a fourth- or fifth-line therapy in that patient with a high disease burden.

Lisa A. Carey, MD, FASCO: Yes, I agree with that. There’s also the issue of, as Lee mentioned early on, some of these patients don’t have HER2-driven breast cancer. Some of the regimens are entirely attached to HER2 protein as the delivery, for example, trastuzumab emtansine needs a HER2-active tumor. This may be less so with trastuzumab deruxtecan and its potential impact on HER2-low breast cancer. But that’s where THP [docetaxel, trastuzumab, pertuzumab] comes in, and if you have a basal-like breast cancer, at least you’re getting free cytotoxic chemotherapy. I think that’s a good point.

Transcript Edited for Clarity