http://www.onclive.com/web-exclusives/hamilton-highlights-treatment-landscape-of-her2-breast-cancer?p=2
Hamilton Highlights Treatment Landscape of HER2+ Breast Cancer

Danielle Bucco

Erika P. Hamilton, MD
Erika P. Hamilton, MD
Patients with HER2-positive breast cancer no longer have as poor of a prognosis due to the development of numerous HER2-directed therapies, explains Erika P. Hamilton, MD.

For example, the December 2017 FDA approval of pertuzumab (Perjeta) in the adjuvant space, which was based on the phase III APHINITY trial, gives another treatment option. Adjuvant treatment with pertuzumab, trastuzumab (Herceptin), and chemotherapy demonstrated a 3-year invasive disease-free survival rate of 94.1% versus 93.2% for those who received trastuzumab plus chemotherapy and placebo. This represented an 18% reduction in the risk of developing invasive disease or death (HR, 0.82; 95% CI, 0.67-1.00; P = .047).

In an interview with OncLive, Hamilton, director of the Breast and Gynecologic Research Program at Sarah Cannon Research Institute, discussed recent FDA approvals in the treatment paradigm of HER2-positive breast cancer and shed light on the prevalence of brain metastases.

OncLive: If a patient undergoes testing and it comes back that they have HER2 expression, what are some of the first things you are thinking about when determining treatment?

Hamilton: We know that HER2-positive breast cancers are more aggressive and tend to grow quicker. However, we now have HER2-directed therapies that make this disease not as poor of a prognosis as it used to be. In many ways, we all dread triple-negative breast cancer much more than HER2-positive breast cancer now, with the advent of improved HER2-targeted agents that have improved outcomes significantly. 

When someone is initially diagnosed with HER2-positive breast cancer, we want to know if we are in the curative or non-curative space. We are then thinking about a chemotherapy backbone in combination with a HER2-directed agent, such as trastuzumab and pertuzumab.

Can you discuss what impact the recent FDA approval of pertuzumab will have on this patient population?

It is exciting that we now have the adjuvant approval. Pertuzumab has been approved in the metastatic and neoadjuvant setting for some time and medical oncologists have been trying to capture those patients before they go to surgery to give them pertuzumab in the neoadjuvant setting. However, sometimes patients go to surgery without seeing a medical oncologist, when their cancer is easily resectable, and they didn’t have the ability to receive pertuzumab after surgery since it hasn’t been approved in the adjuvant setting. It takes the pressure off now that pertuzumab is approved across the board.

Its uptake in the adjuvant space is probably not going to be, nor should it be, 100%. We are learning that there are different subsets of patients that need pertuzumab more than others. Right now, it looks like those 2 subsets are probably the node-positive patients and/or the patients who are also of hormone receptor–negative status. 

Can you discuss the sequencing of agents?

In the neoadjuvant space for patients who are high risk, have a tumor greater than 2 centimeters, or have node-positive disease, we are using a regimen of docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP). In the adjuvant space, we now can use pertuzumab in conjunction with trastuzumab after this approval.

The metastatic setting is where sequencing comes in. It is tricky and will be changing over the next couple of years as more patients receive pertuzumab in the early-stage setting. Currently, our standard algorithm in the first-line setting is paclitaxel, trastuzumab, and pertuzumab (THP). In the second-line space, people receive ado-trastuzumab emtansine (T-DM1; Kadcyla). Third-line and beyond is open as there are many different options and not one standard of care. However, for the patients in the neoadjuvant and adjuvant space who are quickly relapsing on pertuzumab, we likely will not treat those patients with pertuzumab again. We will probably be bringing T-DM1 up. 

This opens the way for new HER2-targeted agents in the second-line and beyond. There are many clinical trials investigating new HER2 compounds.

Can you discuss those emerging HER2 compounds?

One of the things that has been exciting for HER2-positive breast cancer is T-DM1. It is our first antibody-drug conjugate for breast cancer. That is essentially where your chemotherapy is bound or fused together with an antibody. How I like to explain this to patients is it is not “naked chemotherapy.” I call it “naked chemotherapy” when it is infused in the veins and goes everywhere in your body, which can cause adverse events (AEs) in other cells such as hair loss, damage to our infection fighting cells or nerves, or nausea.

There are a lot of new antibody-drug conjugates in development. There are also new HER2 antibodies, similar to pertuzumab. There are new ways to target HER2 in a stronger way than we have thought about before. 

There are multiple companies looking at these compounds. We have several in clinical trials at Sarah Cannon Research Institute right now. We have ones in the phase II/III space, as well as some new antibody-drug conjugates and antibodies in our phase I space.

Oncologists are now able to be smarter by targeting these HER2 cells without dumping a lot of poison or “naked chemotherapy” into the body. Some of these new compounds can target HER2 and get more specific by harming just the cancer cells—like T-DM1, which works well in many patients. Many times, that translates to better tolerability and fewer AEs for our patients.

Can you discuss how prevalent brain metastases are and the best way to treat them?

We have always known that HER2-positive patients are getting brain metastases more frequently than other types of breast cancer. Up to 50% of patients with HER2-positive disease will develop brain metastases at some point in their metastatic course. That is much higher than other cancers, such as estrogen receptor–positive breast cancer.

What has become even more obvious is now that we have more HER2 agents that control disease in the rest of the body, such as pertuzumab or T-DM1, women are living longer with this disease, which gives them longer to develop the brain metastases. We are going to continue to see this more frequently.

A lot of our systemic therapies do not cross the blood-brain barrier very well. Although they are great at controlling systemic disease—or disease from the neck down—they do not do a good job of preventing or treating brain metastases. 

Neratinib (Nerlynx) is a drug that has some potential for brain metastasis treatment. An FDA-approved drug which we have classically used in the metastatic setting for brain metastases is lapatinib (Tykerb). It is often given in combination with capecitabine.

There are new drugs in development for HER2-positive brain disease. One compound I have been working with for a couple years is tucatinib (ONT-380). It is being developed for all women with HER2-positive metastatic disease, but we have specific interest in the brain metastases space. The trial is very inclusive by allowing patients with brain metastases when, oftentimes, these higher-risk patients are excluded from clinical trials. Tucatinib has shown really encouraging activity in brain metastases.

One of the things that is tough when using drugs such as lapatinib or neratinib is that they not only block HER2, but also block HER1 (or EGFR), which can lead to AEs such as rash and diarrhea. What is unusual about tucatinib is that it is HER2-specific and does not block EGFR. Thus, it does not come with a lot of rash and diarrhea and is very tolerable.

At the 2017 San Antonio Breast Cancer Symposium, it was shown in 2 phase I studies that the population of patients with brain metastases did equally well compared with the people that did not have brain metastases. This is surprising and very encouraging, because we have all known that patients with brain metastases can have a poorer prognosis than their counterparts who do not have brain metastases. A drug that has enough brain activity to even the playing field for women with HER2-positive breast cancer and brain metastases is desperately needed. 

Right now, this drug is in a phase III registrational trial with fast-track designation by the FDA. The trial is called HER2CLIMB, which is investigating capecitabine and trastuzumab plus or minus tucatinib. 

Looking at the future, what do you hope to see for the treatment of this patient population?

Like we have seen with the recent approval of pertuzumab, I hope we get to the point where we can use these more efficacious compounds earlier in the disease course in the neoadjuvant and adjuvant setting. This will help us prevent patients from developing metastatic, or incurable disease. In the metastatic setting, we need to be smarter when determining sequencing.

I am mostly excited about these new agents, whether it is an antibody-drug conjugate, an antibody, or a tyrosine kinase inhibitor that is specific to HER2 activity. We are getting smarter in treating HER2-positive metastatic disease without causing as many AEs from chemotherapy that we traditionally have. Having new targeted compounds specific for HER2-positive disease will hopefully continue to enable women to do better for longer with an improved quality of life.

Is there anything else you would like to add?

I would encourage patients to seek out their clinical trial options. We are at a point right now in cancer care where we have so many exciting agents coming, and often the best way to gain access to those drugs is through clinical trials. Whether it is neoadjuvant, adjuvant, or metastatic disease, exploring your clinical trial options is a smart thing to do.
von Minckwitz G, Procter MJ, De Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017; 377:122-131.
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