Optimizing Treatment for Patients With High-Risk HER2-Positive Breast Cancer

In this expert roundtable series, Reshma Mahtani, DO, Miami Cancer Institute, Florida, leads a 4-part discussion on the management of early-stage HER2-positive breast cancer. Participating in the discussion are Terry Mamounas, MD, Orlando Health Cancer Institute, Florida, and Jane Meisel, MD, Winship Cancer Institute, Atlanta, Georgia.

In this video, our experts share insights on optimizing therapy for patients with high-risk HER2-positive breast cancer, sharing their views on anthracycline-based therapies, neratinib, and immunotherapy for these patients, and discussing data from the KATHERINE trial.

Watch episode 4, where our experts discuss 8-year updated results from the APHINITY trial.

Transcript:

Dr Reshma Mahtani: Now let's switch gears in the third section, to talk about optimizing therapy for high-risk patients. Jane, can you start out by giving us your views on anthracyclines and using anthracycline-based therapy in this high-risk population?

Dr Jane Meisel: Yes, as I alluded to in one of the past sections, I'm moving away from using a lot of anthracyclines in this patient population, actually. I think we're seeing really great data from TRYPHAENA and other studies looking at TCHP [docetaxel, carboplatin, trastuzumab, and pertuzumab] and showing just as good pCR rates as we do with anthracycline-containing regimens. That was helpful. Now, we have data from TRAIN-2 and also BCIRG-006 with some long-term follow up showing very similar outcomes in terms of the HER2-directed therapy improving survival and outcomes, but also having fewer cases of secondary leukemias and less cardiotoxicity than anthracyclines.
I am using a lot less AC-THP [doxorubicin plus cyclophosphamide, followed by paclitaxel, trastuzumab, pertuzumab] and a lot more TCHP. The few situations where I don't do that are in situations where the patient is high-grade, maybe HER2 2+ on immunohistochemistry and just over the border on FISH testing, where I suspect that there may be a triple-negative subclone we may not be seeing in the original pathology report.

If the patient is young and healthy, then in those particular patients, I may lean more towards the AC-THP. Again, it's an art as well as a science, but for most HER2-positive patients, TCHP is my go-to neoadjuvant regimen and I’m generally seeing very good outcomes with that. But I do counsel people as Terry mentioned, if you are ER-positive, HER2-positive, your pCR rate might be slightly lower than if you're ER-negative and HER2-positive. So, we have to make sure that we don't set people up for expectations that then can't be met. But I have seen some very good outcomes with this regimen for sure.

Dr Reshman Mahtani: I agree. I'm moving away from the use of anthracyclines in the majority of my patients as well.

Terry, you had brought up the KATHERINE data. We heard updated overall survival data at San Antonio for those with residual disease. Can take us through that trial design and review some of the updated data that we heard about?

Dr Terry Mamounas: Sure. The KATHERINE trial was a trial that evaluated T-DM1 versus trastuzumab, which at the time was the antibody that we used for patients with breast cancer that had residual disease after neoadjuvant chemotherapy, plus anti-HER therapy. The majority of the anti-HER therapy was trastuzumab-based. For about 18% or 20% of the patients, pertuzumab was also used because it was towards the tail-end.

The results originally presented showed a significant improvement in disease-free survival [DFS] which was about a 50% reduction in the rate of events and about an 11% absolute benefit. With more follow up, the data that were presented in San Antonio showed that the DFS benefit has reached almost 13% absolute improvement. In the final analysis now, we also have a significant improvement of overall survival in the range of about 5%.

That was a really exciting piece of information that we managed to see from that trial, because really, as I said before, it allows us to offer patients a good alternative even if they don't get the pathological complete response. That was the hang-up before, that we had nothing to offer. We said, “Well, it's great if you get a pCR, but if you don't, well, your prognosis is worse and we're not going to do anything different.” Now, we have something that improves survival, which I think is very important. An important trial.

And I wanted to comment before, we also use TCHP almost exclusively for patients in the neoadjuvant setting, because the cardiotoxicity issue is much more important. I tell that to the patients I see, because they come in mid-chemotherapy and after chemotherapy to discuss surgical approach, and they're all struggling with a regimen. But it's a short-term pain for long-term gain. And then I try to reemphasize to them, “Yes, but we avoided anthracycline.”

As you mentioned, we only use anthracyclines for patients that have maybe heterogeneous disease or 2 primaries, where one is a HER2-negative and one is a HER2-positive and we want to cover all bases. If it's a straightforward, HER2-positive patient, we use TCHP almost exclusively in our institution.

Dr Reshma Mahtani: Thank you both for those comments. Jane, are you using extended adjuvant neratinib in any of these patients?

Dr Jane Meisel: It's tough. I'm not using as much of it as I did before we had the T-DM1 option. The challenges with neratinib are that after you're done with your year of anti-HER2 therapy, either intravenous or subcutaneous, patients are often a little bit tired and beaten up from all of their treatment. Taking a pill that potentially causes diarrhea that can be significant from a quality-of-life standpoint can be a tough sell.

We also don't know as much about how well neratinib works in a post-THP, post-T-DM1 setting. There is some data there, but not as much from the ExteNET trial about that specific patient population. It’s one of those examples of the trial being done at a time where the standard of care was different than what it is now. It's sometimes harder to extrapolate the data as confidently.

I will say, though, for many patients, especially if you start the neratinib at a slightly lower dose than what's on the package insert, starting at 160 or something like that, you can make the diarrhea fairly manageable. For those patients of mine that say, “I want to do everything I can to cure this disease, is there anything else you can give me?” I have still used it in a handful of folks, but I'm using a little less these days, because we have the T-DM1 option, and a better sense of who needs more upfront chemotherapy.

We're giving a lot more neoadjuvant than I think was given when that trial was initially designed.

Dr Reshma Mahtani: I agree. As you pointed out, some of the challenges with regards to the toxicity management, even with the dose-escalation strategy in certain patients, it's very difficult because you have to have a very highly motivated patient. Especially in someone who's got ER-positive disease, HER2-positive with a lot of residual cancer, I may consider it in that situation, but it is a bit of a tough sell, so to speak.

Terry, maybe you can talk to us about some of the important studies that are currently enrolling in this area, especially with regards to the use of trastuzumab deruxtecan (T-Dxd) in patients that have residual disease. I know the NSABP-B60 trial is something that we could highlight in this space.

Dr Terry Mamounas: As you know, there have been 2 approaches after the KATHERINE data were available, and then tucatinib was found to be of benefit in patients in metastatic HER2-positive breast cancer, as well as T-Dxd. And those are both incorporated in post-neoadjuvant trials. The B-60 trial, as you mentioned, is a trial that compares head-to-head, T-DM1 to T-Dxd for the same duration as in the KATHERINE trial and does so in patients with high risk for residual disease, essentially node-positive for most of the patients. That trial completed its accrual. It's a global trial, and the NSABP was part of that.

On the other side, in the cooperative group system, we have the Alliance A011801 trial which adds tucatinib to T-DM1, based on the results from the metastatic setting. And that trial is still ongoing, we still have a few hundred patients to accrue to this trial, so it's available. There is a similar risk profile, and it will target the higher-risk patients, those that have multiple positive nodes or large residual disease and hormone receptor-negative tumors.
Both these trials will be crucial to extend the benefits that we've seen from T-DM1.Looking at some of the metastatic trials, we’re hopeful that we'll be able to beat T-DM1 with something, either more or instead of, with a different drug.

Dr Reshma Mahtani: Jane, are there any studies that you're watching in this space that haven't been mentioned already? Especially with regards to immunotherapy options?

Dr Jane Meisel: I am also very excited about the potential option of T-Dxd. DESTINY-Breast05 is going to be very interesting in that space. We saw in a metastatic setting how much that made a difference when we looked at T-Dxd versus T-DM1, head-to-head as second-line therapy. It's a drug that also has toxicities, so we'll have to think about if we start using it in curative patients. But if it changes things for people that could be quite interesting.

There are also some studies looking at the use of immunotherapy for these patients. For these highest risk folks that have residual disease at the end, using options like atezolizumab combined with anti-HER2 therapy, which I think will be very, very interesting to see what the results of those studies look like. ASTEFANIA is one of those trials looking at atezolizumab plus trastuzumab emtansine (T-DM1) vs placebo plus T-DM1. The idea that we can build on the T-DM1 backbone that we're currently using in that residual disease setting by adding immunotherapy.

Dr Reshma Mahtani: Are there any biomarkers that either of you are following in this space that have the potential to be helpful? Any gene expression assays or things of that sort to help us tailor our treatments a bit better?

Dr Terry Mamounas: You can think about something like HER2DX, which is a prognostic marker for pCR. The issue is that it includes factors like ER receptors and those are confounders. I'm not sure that we have really come to the point to use this. If I was a HER2 patient, I would want to get anti-HER2 therapy, whether I'm HER2DX high or low. I probably would even if there is a possibility of stratifying the pCR rates. This may be used when you're trying to de-escalate or to pick out some patients who don't respond well to anti-HER2 therapy, because we may have luminal disease, and you see that there are some patients that are not always the HER2 subtype.

HER2 subtype is another one, by profiling, you can look at the HER2 subtype. At the NSABP, we have looked back at the B-31 trial and we found this aging index that predicts benefit from trastuzumab. But it's the same thing, it doesn't rule out benefit from trastuzumab even when you expect lower response. It’s very hard to not treat a patient with anti-HER2 therapy if they are HER2-positive.

Dr Reshma Mahtani: Yeah, agreed.