Hamilton Highlights Progress in HER2-Positive Breast Cancer

Erika P. Hamilton, MD

The treatment landscape for patients with HER2-positive breast cancer continues to evolve, with a potential new FDA approval on the horizon, explains Erika P. Hamilton, MD.

The FDA recently granted a priority review designation to a supplemental biologics license application for pertuzumab (Perjeta) for use in combination with trastuzumab (Herceptin) and chemotherapy for the adjuvant treatment of patients with HER2-positive early breast cancer.

With emerging options and established treatments, a challenge will be determining the correct sequence of systemic agents to give patients the maximum benefit with the least significant adverse events.

“The past several years have been exciting for HER2-positive breast cancer,” said Hamilton. “We had the approval of TDM-1 (ado-trastuzumab emtansine; Kadcyla), pertuzumab, neratinib (Nerlynx), and possibly more drugs over the next few years. For women who are going to be diagnosed with HER2-positive breast cancer and for those who have it now, it’s an exciting time for treatment.”

“A remaining challenge is that we have enough drugs, but we need to determine how to best sequence them. Whether we need to use them in combination or in sequence, it is important to determine the maximum benefit from them,” said Hamilton.

OncLive: Can you provide an overview of your presentation?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Breast Cancer, Hamilton, director of the Breast and Gynecologic Research Program at Sarah Cannon Research Institute, discussed the current treatment landscape for patients with HER2-positive breast cancer.Hamilton: I provided updates in HER2-positive breast cancer, particularly in the early-stage setting, as well as the neoadjuvant and adjuvant data. We’ve recently received word that pertuzumab is on fast track for approval for consideration in early 2018 for adjuvant therapy.

Can you further discuss the potential with neratinib?

What is the role of extended adjuvant therapy?

I also discussed neratinib, which is a HER2-specific tyrosine kinase inhibitor (TKI) and the data in the adjuvant space after 1 year of trastuzumab. I [spoke on] some of the newer agents under investigation particularly for HER2-positive brain metastases, which is an area of unmet clinical need for women right now. Neratinib is an oral HER2-positive TKI. It is similar to lapatinib (Tykerb), it’s FDA approved, and it’s a pill that women take at home that blocks HER2. Specifically, the trial that resulted in neratinib’s approval (ExteNET) looked at neratinib versus placebo in women who had already completed their 1 year of adjuvant trastuzumab and they continued treatment for another year. Data showed that there was [about a] 2% improvement [with neratinib versus placebo] in women who did not see their cancer come back during that time frame. The role of extended adjuvant therapy in HER2 may not be quite as clear cut as estrogen receptor—positive disease, but there is a benefit. For those women who have a higher risk and are motivated, it is a reasonable option.

What are some of the newer agents for patients with brain metastases?

It is important to be careful with neratinib due to the toxicity, as there is significant diarrhea [associated] with this drug. For women who are having trouble tolerating it despite antidiarrheals, or for women who do not have a high risk for recurrence, it may not be worth it in this setting. However, for women who are high risk and can tolerate it, it is a valuable option.One of the newer agents is a drug called tucatinib, previously known as ONT-380. It is a TKI but, as opposed to neratinib and lapatinib, it only blocks HER2 and does not block HER1 or EGFR. The side effects of neratinib and lapatinib, such as rash and diarrhea, come from blocking HER1.

What are other emerging agents are you excited about in HER2-targeted therapy?

This is a pill that easily gets across the blood-brain barrier, making it work well in brain metastases and is generally well tolerated for women. Currently, it is in a registration, randomized trial with capecitabine and trastuzumab (Herceptin) that is open at Sarah Cannon Research Institute. We are excited about the drug. Some of the drugs we are excited about are the next generation of antibody-drug conjugates, such as T-DM1. This was our first antibody-drug conjugate for HER2-positive breast cancer and has revolutionized the way we have treated that disease in the metastatic setting. In our phase I unit, we have multiple other drugs targeting HER2. These antibody-drug conjugates are exciting—not only for us, but for patients because it attaches chemotherapy payload onto an antibody that only targets HER2. As opposed to the entire body getting the side effects, it targets the cancer cells and delivers that chemotherapy directly on the cancer cell itself. It can be very efficacious but spares side effects.

What are some of the remaining challenges in HER2-positive breast cancer that you want to see tackled?

That has been the theme of the past couple of years. We have so many agents for breast cancer that we are not only answering the question of what works, but what works well that can spare side effects. A remaining challenge is that we have enough drugs but we need to determine how to best sequence them. Whether we use them in combination or in sequence, it is important to determine the maximum benefit from them.

Other challenges are in regard to brain metastases. We know that as these women live longer with HER2-positive metastatic disease, chemotherapy and targeted agents don’t cross into the brain very well. Brian metastases are going to become more prevalent the longer these women respond well to treatment. We are going to need more agents to combat that moving forward.