In this expert roundtable series, Ruta Rao, MD, Rush University, Chicago, Illinois, leads a 3-part panel discussion on the management of patients with HER2-low metastatic breast cancer with William Gradishar, MD, Northwestern University, Chicago, Illinois, and Seth Wander, MD, PhD, Massachusetts General Cancer Center, Boston, Massachusetts.

In the final part of this discussion, our experts talk about the use of trastuzumab deruxtecan in HER2-positive metastatic breast cancer, including data presented at the 2024 ASCO Annual Meeting.

Transcript:

Ruta Rao, MD: Welcome back to the Oncology Learning Network. My name is Ruta Rao, and I am joined by Dr William Gradishar from Northwestern Feinberg School of Medicine and Dr Seth Wander from Massachusetts General Cancer Center.

In this segment, we will shift gears a little bit and focus on T-DXd in HER2-positive metastatic breast cancer. Maybe we can start earlier and say what is your general approach to HER2-positive metastatic breast cancer?

Seth Wander, MD, PhD: I would comment first that we've made tremendous progress in treating patients with metastatic HER2-positive disease with really incredible improvements in overall outcome.

I think the current standard of care today would still be first-line treatment per the CLEOPATRA regimen with a taxane and dual antibody blockade, with trastuzumab and pertuzumab. Based upon the DESTINY-Breast03 study, which I think we'll discuss in a moment here, we would typically then utilize trastuzumab deruxtecan in the second-line setting.

Of course, as time goes on, we have other opportunities to utilize HER2-directed kinase inhibitors, conventional chemotherapy in combination with Herceptin [trastuzumab], integrating optimal ER-directed therapy for those patients that are both hormone receptor-positive and HER2-positive.

Dr Rao: And Bill, can you tell us a little bit about the updated DESTINY-Breast03 trial results?

William Gradishar, MD: That data is impressive. It was impressive the first time we heard it, a comparison of [trastuzumab emtansine] TDM-1 to trastuzumab deruxtecan. And all the end points that we look at as oncologists were markedly improved. If you look at median PFS, it was triple, basically, what we see with TDM-1. The response rate was longer. Survival is also numerically significantly longer with T-DXd. And then finally, if you did respond, the duration of that response was significantly extended. Again, I would make the same comment, that all of these parameters are clinically relevant, and they're moving in a very clinically relevant magnitude.

Dr Rao: To Seth's first point, we've made some significant advances with our first and second lines of therapy in HER2-positive metastatic breast cancer.

What future data sets are you looking forward to? What drugs or sequences or combinations?

Dr Wander: I think we still need to learn more about some of these next generation HER2-kinase inhibitors. These drugs, again, are oral. It would be nice to have the opportunity to use them in the least toxic regimen possible. In the case of tucatinib, for example, we traditionally have given it in combination with capecitabine. mIt would be wonderful to be able to utilize these drugs similar to how we utilize targeted oncogenic directed therapies in ER-positive, HER2-negative disease.

Moving forward taking some of these newer antibody drug conjugates that we've been discussing today and thinking about combining those with some of our emerging therapies. That could be a kinase inhibitor, it could be a next-generation antiestrogen, it could be immune therapy. These may provide new opportunities for durable, tolerable treatment regimens. Of course, we have to watch for all of the rare but significant toxicities that might arise with strategies like that.

As we move forward, merging some of these parallel, development pathways together. We have all these new anti-estrogen therapies, we have all these new and emerging targeted therapies, we have all these new and emerging ADCs. We need to think about how these tracks will begin to cross. How should these agents be combined? How should these agents be sequenced? Not just ADC-to-ADC, but next-generation anti-estrogen and targeted agents as well as ADC. And that's going to take a number of years to tease apart, but I think it will provide excellent opportunities for patient care across the spectrum of these treatments.

Dr Rao: Absolutely.

Dr Gradishar: And the only thing I would add is that, again, to your point, we appreciate there's heterogeneity in tumors. So, the fact that they're HER2-positive, there may still be other populations of cells. All these drugs we're developing and how we use them, may make more sense understanding that the biology is not a homogeneous group of cells throughout. There may be a mixture of those that are ER-positive. We may also learn that we can enhance the effect of the drugs we have available, T-DXd, by partnering it with who knows what: immunotherapy, PARP inhibitors, whatever. There is a rationale, at least pre-clinically, for doing a lot of these things, whether it bears fruit will be determined by clinical trials.

The one other trial that I'm interested in, I know it's somewhat off-topic, is the residual disease T-DXd versus TDM-1 (DESTINY-Breast05). And if that looks the same as DB-03, then we may make a major impact on patients that have high risk of developing metastatic disease.

Dr Rao: What unmet needs do you think we have in the HER2-positive metastatic breast cancer space?

Dr Wander: Survivorship is becoming an increasing important challenge. For example, all of us who treat a lot of breast cancer patients have examples of patients with metastatic HER2-positive disease who can do extremely well, even for decades — Can we safely de-escalate some of those patients, off of more toxic therapies onto maintenance regimen or even off of therapy? This is an important unmet need.

We're developing also tools to monitor minimum residual disease. Bill mentioned thinking about optimal ADC treatment for patients with traditional measures of residual disease, post-neoadjuvant chemotherapy, for example. But now we also have these molecular tools where 6 months later, a year later, 5 years later, you can find circulating tumor DNA as a sign of disease recurrence. What do we do there? This is a really important unmet need not just for HER2-positive but for all patients.

How do we identify patients at risk of progression, even before they have clinical symptoms or scans? How do we identify patients who are going to have long-term indolent disease and we can use effective and safe de-escalation strategies? I think these are both important, mutually exclusive topics for breast cancer in general including HER2-positive.

Dr Rao: Great, thank you.

Dr Gradishar: And the only thing that I would add as well is thinking about the availability of these drugs. Of course, worldwide, that's not going to happen overnight. But even within our own borders, we know that patients don't have access to all the same things. There's one of the presentations looking at the frequency of NGS testing and the utilization of PI3 kinase inhibitors, if appropriate. And as you might predict, in certain populations, the African American population, it's much less than other populations. My guess is that if you looked at the utilization of these newer drugs in similar populations, you might find that there are some disparities and inequities.

Dr Rao: Thank you both very much for this exciting discussion on T-DXd in HER2-positive metastatic breast cancer. And this concludes our discussion series.

Thank you both for participating and thank you to the Oncology Learning Network for organizing this talk. Please check out www.oncnet.com to catch the rest of this discussion as well as other updates on cancer care.

Source:

Swain SM, Baselga J, Kim S-B, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-734. doi:10.1056/NEJMoa1413513

Hamilton EP, Hurvitz S, Im S-A, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): Updated survival results of DESTINY-Breast03. Presented at the 2024 ASCO Annual Meeting. May 31-June 4, 2024; Chicago, IL. Abstract #1025.

Cortés J, Kim S-B, Chun W-P, et al. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med. March 23, 2022;386:1143-1154. doi:10.1056/NEJMoa21150