Trastuzumab Deruxtecan for Patients With HER2-Low Metastatic Breast Cancer

Erika Hamilton, MD, director, Breast and Gynecologic Cancer Research Program, Sarah Cannon Research Institute, Nashville, TN, discusses the recent FDA approval of trastuzumab deruxtecan, a HER2-directed antibody drug conjugate for the treatment of HER2-low metastatic breast cancer. This approval was based on results from the phase 3 DESTINY-Breast04 trial which demonstrated a reduced risk of disease progression or death for patients treated with trastuzumab deruxtecan compared to chemotherapy.

Trastuzumab deruxtecan was approved by the FDA on August 5, 2022, for the treatment of patients with HER2-low metastatic breast cancer who had previously received chemotherapy in the metastatic setting or have developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.

Transcript:

What is trastuzumab deruxtecan?

Dr Hamilton: Trastuzumab deruxtecan is a HER2-targeted antibody-drug conjugate, and it was first approved for HER2-positive metastatic breast cancers, and more recently, and what we are talking about today, is a new indication for cancers that are HER2-low. But essentially the drug is a HER2-targeting antibody that is joined to a payload through a linker, and the drug-to-antibody ratio for trastuzumab deruxtecan is around eight.

What data led to this approval in this population?

Dr Hamilton: Approval was based on the DESTINY-Breast04 study. This population of patients were what we would typically classify as triple-negative, or hormone receptor positive, but they had HER2-low expression. This is not HER2 IHC3+ or FISH-amplified. These are patients that are traditionally considered HER2-negative but have 1+ or 2+ IHC expression. In the trial, trastuzumab deruxtecan was compared to treatment of physician's choice of chemotherapy— standard, single-agent chemotherapies that we would typically give patients with these type of cancers—and trastuzumab deruxtecan significantly outperformed them. The progression-free survival for the patients that had hormone receptor positive disease that was HER2-low was 5.4 months with traditional chemotherapy, and over 10 months with trastuzumab deruxtecan. For the small percentage of patients that had what we would typically consider triple-negative disease, the magnitude of benefit really looked just as good, although this was a very small number. For those patients, progression-free survival improved 2.9 months with chemotherapy up to 8.5 months with trastuzumab deruxtecan.

What is the current treatment landscape for patients with this metastatic HER2-low breast cancer?

Dr Hamilton: These patients are typically treated with standard, single-agent chemotherapy. For triple-negative breast cancer, we have immunotherapy approved first-line for the patients that have PD-L1 positivity, but after that, patients have sacituzumab, which is another antibody-drug conjugate that is currently approved, and otherwise they receive single-agent chemotherapy. Our patients with hormone receptor positive disease are typically treated with endocrine therapies, and then once they exhaust endocrine therapies or are no longer getting benefit from them, they move on to chemotherapy and are treated in a very similar way as triple-negative, once the hormone agents are not working anymore.

It was really encouraging to see that progression-free survival was so much longer with trastuzumab deruxtecan, especially in those patients with only low HER2 expression compared to chemotherapy. And we also certainly saw an overall survival benefit, over 6 months for the hormone receptor positive patients and a little over 10 months for those patients with triple-negative breast cancer. What that means is that our patients are living longer when they receive this drug as opposed to just chemotherapy.

How does trastuzumab deruxtecan fit into the current treatment paradigm?

Dr Hamilton: Yeah, so this trial was for hormone receptor positive patients who had exhausted endocrine therapy and received chemotherapy. And for our triple-negative patients, they had also already been treated with chemotherapy. This is not a first-line treatment option. It is for patients have already seen chemotherapy and had their disease progress.

What is the safety profile of trastuzumab deruxtecan?

Dr Hamilton: The good news for trastuzumab deruxtecan is that it is not a new drug for the breast medical oncology community. We have been using it for several years now for patients that have HER2-positive disease, so we are familiar with how to give it and what the side effects are. The most common side effect is nausea, it is considered to be a moderately emetogenic drug. In the United States, we typically prescribe prophylaxis agents for nausea, in a 3-drug regimen: a 5-HT3; steroids, often dexamethasone; and an NK1. We titrate from there — for patients that are still experiencing nausea, we add something else and for patients that really are not having any nausea, maybe we can peel some of those agents back. But nausea is typically the thing that we see right out of the gate, in cycle 1 or cycle 2. It does not really get any worse with cumulative treatment if patients are on it for longer, but it is something we have to manage.

Certainly we can see things like fatigue with antibody-drug conjugates. We see alopecia, or hair loss, in some of our patients here, so that is important to let patients know so they are not surprised about hair loss, especially since it is an antibody-drug conjugate, and some of our other antibody-drug conjugates, like T-DM1, we do not see a whole lot of hair loss.

And then the special side effect that we really try to keep in mind is interstitial lung disease (ILD) or pneumonitis, inflammation in the lungs. This happens, depending on what study you are looking at, in about 10% to about 13% of patients. In the DESTINY-Breast03 update, so our data for the HER2-positive patients, our discontinuation rate due to ILD/pneumonitis is about 8% for patients. There have been several cases of fatal pneumonitis. We saw a couple in this study. We are not seeing any in DESTINY-Breast03 now. We did see some in DESTINY-Breast01. It is something to be aware of and make sure that we know that we are holding drug for grade 1 asymptomatic pneumonitis seen on a scan. If that goes away and improves within 28 days, we can re-challenge with drug. But for grade 2 pneumonitis that is symptomatic or worse, we stop the drug and do not re-challenge. And with these increased guidelines and awareness, we have really been able to cut down on any of the severe cases of ILD/pneumonitis.

Do you think this approval will have an immediate impact in real-world practice?

Dr Hamilton: I absolutely do. I think that the data are compelling. It is a drug that we know how to give. It is given intravenously every 3 weeks. And really, overall survival data is quite compelling. I think the challenge in implementation for this drug, a temporary challenge that we will adjust to and get quite better with, is identifying those patients that have an IHC of 1+ or 2+ and are HER2-low. Previously, HER2-low has not been a designation that we look at or think about in clinic. Patients either have ER-positive breast cancer, triple-negative breast cancer, or HER2-positive AKA high breast cancer, because HER2-low has not been actionable.

One, we have to educate our pathologists that an IHC of 1+ is actionable now, because previously only a 3+ was actionable, and 0s, 1s, and 2s all got lumped in the negative bucket. Now that we have this new designation of HER2-low, we need our pathologists to help us identify those patients. And then second, as medical oncologists, we need to start capturing this in our documentation. A lot of notes just say, "triple-negative" and do not mention if the HER2 is low. “Negative” is kind of going away. Patients have tumors that are HER2-0, HER2-low, or the HER2-positive with high expression. Capturing in our notes the IHC values now, the 1+s and 2+s, and starting to use this HER2-low terminology to make sure that we do not miss anyone that would be eligible for this drug and are certainly offering it to our patients is going to be very important.

What are next steps for investigating trastuzumab in this population or other breast cancer populations?

Dr Hamilton: There are a lot of trials ongoing. Since we have seen the approval of trastuzumab deruxtecan for select gastrointestinal cancers, and most recently for a population of patients with lung cancer, trastuzumab deruxtecan is being looked at in other tumor types that commonly do have some HER2 expression, which can be a lot of tumor types.

In the breast cancer realm, we are looking at this in earlier line, specifically for our patients that are HER2-positive. There are ongoing trials against T-DM1 for residual disease in curative-intent neoadjuvant treatment, where if the patients have residual disease, they are randomized to receive T-DM1 or trastuzumab deruxtecan for residual disease. There are trials looking at trastuzumab deruxtecan first-line. It now has approval in the second line, so this is looking at moving trastuzumab deruxtecan earlier up. And there are certainly combinations with a variety of agents, combinations with endocrine therapy, or with targeted medicines, or with even immunotherapy. It is exciting to see all the places that this drug may end up