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Blackwell Discusses Emerging HER2-Positive Breast Cancer Agents

Gina Columbus @ginacolumbusonc
Published: Monday, Oct 19, 2015

Kimberly L. Blackwell, MD

Kimberly L. Blackwell, MD

Emerging therapies are advancing through the pipeline in HER2-positive breast cancer, potentially giving oncologists options beyond some of the current treatments, such as pertuzumab (Perjeta), trastuzumab (Herceptin), and ado-trastuzumab emtansine (T-DM1; Kadcyla).

Excitement is building from a phase I study that looked at margetuximab (MGAH22-01), a HER2-targeting monoclonal antibody engineered for increased Fc-domain binding. The agent demonstrated significant response rates among patients with heavily pretreated breast cancers, including four patients with confirmed partial responses still ongoing at the time of the analysis and lasting from >10 weeks to >100 weeks.1

In a recent phase III study, the tyrosine kinase inhibitor neratinib administered to patients immediately following adjuvant trastuzumab plus chemotherapy improved invasive disease-free survival (DFS) against placebo at the cost of low-grade diarrhea in nearly all patients with HER2-positive early-stage breast cancer. The 2-year invasive DFS rate was 93.9% in the neratinib arm versus 91.6% with placebo, representing a 33% reduction in the risk of recurrence (HR, 0.67; 95% CI, 0.50-0.91; P = .009).2

Additionally, researchers are also hopeful with the small-molecular HER2 inhibitor ONT-380, shown to have promise in previously treated metastatic patients with CNS metastases.

Moreover, long-term follow-up results from the phase III CLEOPATRA trial, which examined the safety and efficacy of pertuzumab, trastuzumab, and chemotherapy in patients with previously untreated HER2-positive metastatic breast cancer, showed a 16-month survival benefit3 compared to those who received trastuzumab and chemotherapy alone, demonstrating the efficacy with pertuzumab and validating it as a standard of care, explains Kimberly L. Blackwell, MD.

In an interview with OncLive, Blackwell, professor of Medicine, assistant professor of Radiation Oncology, Duke Cancer Institute, discusses the potential for these emerging therapies, as well as the benefits of current treatments for patients with HER2-positive breast cancer.

OncLive: What are the some of the up-and-coming, novel therapies for HER2-positive breast cancer?

Blackwell: There is a new way in how we target HER2, including new antibodies, margetuximab, which is a high-affinity HER2-antibody that we think stimulates the immune system even better than trastuzumab does. There is updated pertuzumab data, as well as data showing promise with small-molecule inhibitors. There has been a lot of talk about the ExteNET study looking at adjuvant neratinib. Also, there is ONT-380, which is another small-molecule inhibitor in development. Bringing it all home, there is talk about antibody-drug conjugates, including T-DM1, and another compound, which has encapsulated doxorubicin.

Can you go into greater detail about margetuximab and its potential?

It is actually a very cool antibody. The constant domain of the antibody which, if you think of the fork of the antibody and then the tail, the constant domain has been changed by approximately 5 amino acids. It stimulates natural killer cells and tumor-associated macrophages more, and inhibits the inhibitory immune cells less. Therefore, the net effect is more stimulation of the anticancer immune effector cells, and less inhibition of the immune inhibitory cells. Hypothetically, it should offer a more vigorous immune response against HER2.

We just received the phase I/II data at the 2015 ASCO Annual Meeting, but that is moving into a fairly interesting go/no-go clinical trial that is currently available. The way that the trial is being designed is that it is not actually for classically defined HER2-positive breast cancer. It is actually for what we call equivocal or borderline HER2. These are tumors that are HER2+ positive and are not amplified. There is this idea that if you have a higher affinity antibody against HER2 that stimulates the immune system, margetuximab might benefit those patients who have some HER2 overexpression, but are not necessarily eligible in any classic way for trastuzumab.

What can you share regarding updated data on pertuzumab in HER2-positive disease?

To give a presentation in 2015 without presenting the 16-month survival benefit from pertuzumab, I would be leaving out a major advancement in the field.

I think most of us are at a point where adding pertuzumab in first-line metastatic breast cancer is now a, if not the, standard of care. It is pretty exciting to see that we are helping women live longer with the addition of a monoclonal antibody.

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