Trastuzumab Deruxtecan Expands Metastatic Breast Cancer Treatment Landscape Across HER2-Expressing Subtypes

With the introduction of fam-trastuzumab deruxtecan-nxki (Enhertu), the HER2 status of all patients with metastatic breast cancer must be closely examined to determine the optimal individual treatment courses, according to Jane Lowe Meisel, MD. She emphasized the benefits of targeting HER2 in a large population of patients that has historically been classified as having HER2-negative disease.

“HER2-low breast cancer has previously been a heavy area of unmet need, and now has a drug that is well tolerated, convenient, and works well to improve progression-free survival [PFS] and overall survival [OS] in this patient population,” Meisel said.

In an interview with OncLive®, Meisel discussed the emergence of HER2-low as a new category in breast cancer, outlining the significance of the phase 3 DESTINY-Breast04 trial (NCT03734029) and the unique qualities of trastuzumab deruxtecan in the HER2-positive and HER2-low populations. Meisel also stressed the importance of reclassifying certain patients’ breast cancers as HER2 low in light of these data and postulated what these findings could mean for the triple-negative breast cancer (TNBC) population, as well as for HER2-expressing cancers beyond breast cancer.

Meisel is an associate professor in the Department of Hematology and Medical Oncology and an associate professor in the Department of Gynecology and Obstetrics at Emory University School of Medicine.

OncLive^®: What key findings arose from the DESTINY-Breast04 trial, and how do they redefine the breast cancer subtypes?

Meisel: HER2 low emerged as a new category in breast cancer with the presentation of the DESTINY-Breast04 study, which looked at a new drug, trastuzumab deruxtecan, which we’ve been using for a few years in HER2-positive breast cancer. The DESTINY-Breast04 trial compared trastuzumab deruxtecan with standard single-agent chemotherapy in patients who had HER2-low breast cancer.

HER2 status on breast cancer is checked with immunohistochemistry [IHC]. Traditionally, if a patient had high levels of HER2 expression, 3+, on IHC, they would be HER2 positive. If they were 0 or 1+, they were HER2 negative. If they were 2+, which is intermediate, then [they would receive additional] testing to determine positive or negative [HER2 status].

This study took patients who were had low levels of HER2 expression on IHC, previously defined as negative, those patients with 1+ or 2+ on the confirmatory test, and redefined them as HER2 low to see if trastuzumab deruxtecan would work for them. The study found that trastuzumab deruxtecan, which is a HER2-directed antibody-drug conjugate [ADC], was much better at improving PFS and OS in patients with HER2-low disease.

Most of the patients in this study were also estrogen receptor [ER] positive. However, there was a small number of patients who were ER and progesterone receptor negative but HER2 low, who also seemed to benefit from this drug.

This ushers in a new era where we need to be looking at HER2 status more closely. Instead of how we traditionally defined it, which was positive or negative, there’s positive, and there’s truly negative, which is the HER2 IHC with 0 expression. Then, there’s this much larger category of patients who are HER2 low who may benefit from drugs like trastuzumab deruxtecan.

Before the DESTINY-Breast04 trial, a big unmet need existed for patients with HER2-low breast cancer. What is unique about trastuzumab deruxtecan in this population that makes it effective?

ADCs are an exciting new way of treating cancer. The way these drugs work is by taking a chemotherapy drug and conjugating it to an antibody that then can go seek out cells that overexpress that antigen. In this case, HER2 is the targeted antibody.

What’s unique about trastuzumab deruxtecan is that it has a high drug-to-antibody ratio. Because these cells are being delivered to the HER2-positive cancer cell, you can give higher, more potent doses of chemotherapy than if you were giving chemotherapy without directing it toward a cancer cell like that. That’s 1 reason why it’s so effective.

Additionally, particularly in these patients with HER2-low disease, this drug has membrane permeability. If a patient has a clump of cancer cells, some of which are expressing HER2 but others of which are not, this antibody delivers the chemotherapy to the HER2-positive cancer, and the membrane permeability allows that potent chemotherapy to go into that HER2-positive cell and kill it, but also bypass cell membranes and go next door to the next cancer cell and kill that one, too.

The membrane permeability, combined with the high drug-to-antibody ratio and chemotherapy potency of the ADC, make it so effective, not just in the HER2-positive population, but also in these patients with HER2-low breast cancer who have more tumor heterogeneity.

Could you speak to the potential for this agent’s efficacy in the HER2-negative population as well?

The question will be: Where does this end? This drug may be good for patients regardless of their HER2 status. That also brings up an important question about defining these patients, because HER2 IHC is a bit difficult [to interpret], and sometimes [results] differ from observer to observer or based on which slide you look at. In the [phase 2] DAISY trial [NCT04132960] and some other studies that will be forthcoming, we may see that it’s an option even in the HER2-negative population.

What guidelines or recommendations may come forth regarding the standardization of assessing HER2, as defining HER2 status is so variable?

We’re going to [need to standardize this], because this is going to become such a huge issue for so many patients. We estimate that probably two-thirds of our patients with ER-positive disease are actually HER2 low and were previously defined as HER2 negative. A big group of patients with metastatic breast cancer are going to benefit from this.

In the hormone receptor [HR]–negative population, probably a smaller proportion, we estimate maybe a third of patients with HER2-negative breast cancer will be reclassified as HER2 low. Given how many patients have metastatic breast cancer in the United States and in the world, this is going to be a big issue for pathologists.

We will probably see further standardization of this as time goes on and as we see additional drugs. Trastuzumab deruxtecan is the only drug right now that’s been shown definitively to work for HER2-low breast cancer. There are some reasons why we think that’s the case, and other ADCs out there are being studied that may also be helpful for this population in the future. We will definitely hear more about this.

With the results of DESTINY-Breast04, trastuzumab deruxtecan has become a standard for the ER-positive population. However, given that the ER-negative population was such a small cohort in that trial, where do you think the agent stands there?

It probably still has a place. Patients with TNBC often, unfortunately, progress quickly through multiple lines of chemotherapy and need better options. I get asked frequently about the sequencing of ADCs, because we now also have sacituzumab govitecan-hziy [Trodelvy] on the market, which has been approved based on the [phase 3] ASCENT trial [NCT02574455] data in TNBC. [The phase 3] TROPiCS-02 trial [NCT03901339] was a recent study in heavily pretreated patients [with HR-positive, HER2-negative breast cancer] that also showed a benefit for that agent over chemotherapy.

In patients with TNBC, there’s still much data from the ASCENT trial, [which looked at] many patients, so I would use sacituzumab govitecan first. But if I had a patient who had been through chemotherapy, immunotherapy if appropriate, PARP inhibitors if appropriate, and sacituzumab govitecan, and they still had a good performance status and were HER2 low, I would absolutely use trastuzumab deruxtecan, given the data that we see. I would talk to the patient about the fact that the numbers were small, but the data seem promising.

Trastuzumab deruxtecan tends to be a fairly well tolerated drug, and it’s only [administered] once every 3 weeks, which is a palatable dosing schedule for patients. It doesn’t cause much neutropenia, which is also fantastic for these heavily pretreated patients. I would definitely discuss it with my patients with TNBC and absolutely consider giving to them in later lines of therapy.

What future directions would you like to see for trastuzumab deruxtecan and other ADCs in HER2-low breast cancer?

Any drug that works well in later lines of treatment often gets studied earlier on, such as earlier on in the metastatic setting, and maybe even in patients up front. How much better than chemotherapy will this be? Could this be [a treatment] that, if incorporated properly, could potentially lead to more cures?

Additionally, we’ve made so many strides with HER2-positive breast cancer, and we’ve now seen, with HER2-positive endometrial cancer, for example, that trastuzumab [Herceptin] combined with chemotherapy is better than chemotherapy alone. I wonder about these other HER2 inhibitors in HER2-positive, or now with these data, HER2-low cancers of other subtypes. Will this be [an agent] that can be useful in tumors of other organs of origin as well? There’s much to be studied here, and potentially many benefits for patients everywhere.

What main message would you like to leave with colleagues regarding this topic?

This is a promising area of research. Based on the exciting data we’ve seen, it’ll be interesting to see if this drug can be used earlier or in different settings for HER2-low breast cancer.

Because of this success, we will have to work hard at redefining what HER2 low means and making sure oncologists, not just breast oncologists, but oncologists who see breast cancer anywhere, know that they need to go back and look at their patients’ pathology reports to see if HER2 negative is really HER2 negative or if it’s HER2 low, so that all patients who have the potential to benefit from this drug can benefit from it. Because the mechanism of this ADC is so exciting, with high drug-to-antibody ratios and membrane permeability, maybe other drugs will come on the market as well that can target [HER2] and help patients live longer and do better.