Development of Novel HER2-Targeted Therapies Could Help Reshape Treatment for HER2+ Breast Cancer

Fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and other novel antibody-drug conjugates (ADCs) currently under development have represented key change in the treatment landscape for HER2-positive breast cancer, and other novel HER2-targeted therapies could also bring further change to the space, according to Kelly E. McCann, MD, PhD.

“We have to think about how can we optimize care by sequencing these therapies. There have been numerous clinical trials to go into that in more detail," McCann said in an interview with OncLive®.

In the interview, McCann, a breast medical oncologist and an assistant clinical professor of medicine at the University of California, Los Angeles Health David Geffen School of Medicine, discussed the evolving role of HER2-targeted therapies, the impact of ADCs on treatment, and emerging strategies for managing HER2-positive disease.

OncLive: How has the HER2-positive breast cancer treatment paradigm evolved in recent years?

McCann: HER2-positive breast cancer has had a lot of new treatments develop over the last few years. One of those is T-DXd, another is the tucatinib [Tukysa] regimen from the [phase 2] HER2CLIMB trial [NCT02614794], and a third is margetuximab [Margenza]. We've had 3 great new drugs [that have] revolutionized how we are treating patients.

How have ADCs like T-DXd altered the HER2-positive breast cancer treatment paradigm?

[The] first ADC that was approved for HER2-positive breast cancer was ado-trastuzumab emtansine [T-DM1; Kadcyla], which has been a wonderful therapy. We have a new one, T-DXd, which is very different from T-DM1 in a number of different ways. One is that the ADC gets taken into the cell, the chemotherapy is released in the cell, and for T-DXd, it diffuses back outside the cell. [This] is called the bystander effect. [which] kills cells in the vicinity. That's unlike T-DM1 emtansine, where the chemotherapy stays inside of the cell. There's also a higher potency of drug attached to the antibody [with T-DXd], which is trastuzumab for both ADCs.

Beyond chemotherapy and ADCs, how have other classes of drugs fit into this treatment paradigm in recent years?

One of the big challenges in treating patients with HER2-positive breast cancer is that they can develop brain metastases later on [in the disease course]. This is challenging because we don't have a lot of therapies that cross the blood-brain barrier. We do have TKIs that target HER2—some of them are pan-HER inhibitors such as neratinib [Nerlynx]—but the tucatinib regimen was unique in that it was studied in the HER2CLIMB trial, and there were at least 40% of patients who had known brain metastases going into that trial. That's traditionally not a population that is allowed [to enroll] in trials, and [these patients are] certainly not the majority of the patients in a trial.

The efficacy of these TKIs, in combination with capecitabine, for example, has really revolutionized how we treat our patients with brain metastases. There's also increasing evidence that T-DXd can also cross the blood-brain barrier. It might be because when those drugs get into the cell and the payload is released, that is what diffuses out and crosses the blood-brain barrier, rather than the ADC itself.

Is there any ongoing research with novel agents that could improve precision medicine in this space?

There are a number of new antibodies [being developed] for [HER2-positive disease], such as bispecific antibodies that target the same antigens that trastuzumab [Herceptin] and pertuzumab [Perjeta] target. There are a number of other types of ADCs that have different payloads, which is something that we need to focus on right now. T-DXdand sacituzumab govitecan-hziy [Trodelvy] both [have] topoisomerase I inhibitor [payloads], and it would be great to have other types of payloads in our ADC technology.

ADCs seem to be better than chemotherapy in a lot of ways. They deliver more of the chemotherapy directly to the cell. They seem to have a long half-life, so they stick around in the body for a lot longer than when patients are given chemotherapy. In breast cancer in particular, we don't use topoisomerase I inhibitors in the curative setting. When patients are getting [multiple lines] of chemotherapy, we have to think about what they have been exposed to in the past [in order to] go forward and give them something that their cancer hasn't seen and is less likely to be resistant to.

How could hormone receptor (HR) status affect the treatment of HER2-positive breast cancer?

HR-positive, HER2-positive breast cancer is different biologically than HR–negative, HER2-positive breast cancer. These medications that we're developing in the HR-positive space, such as PIK3CA and CDK4/6 inhibitors, may have a role to play in the future in treating our HER2-positive patients if they have estrogen receptor–positive [disease] as well.

When we look at statistics from the SEER database, and we look at studying those two types of cancers—HR-positive, HER2-positive, and HR-negative, HER2-positive—we can see that there's a difference in how aggressive those cancers are. There's a difference in prognosis, and there's a difference in some of those cancers.