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Neratinib Offers Hope in Treatment of CNS Metastases in HER2+ Breast Cancer

Angelica Welch
Published: Wednesday, Oct 25, 2017

Rachel A. Freedman, MD
Rachel A. Freedman, MD
About 50% of patients with metastatic HER2-positive breast cancer will eventually develop central nervous system (CNS) metastases at some point in their treatment course.

, lead study author Rachel A. Freedman, MD, associate clinical director, Breast Oncology Center, Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, discussed treating patients with HER2-positive breast cancer who develop CNS metastases, and the promise that neratinib holds in this patient population.

OncLive: Can you provide an overview of this study of neratinib and capecitabine in HER2-positive breast cancer?

Freedman: Patients with HER2-positive breast cancer that is metastatic have a high likelihood of developing CNS metastases. Many women will continue to progress in their CNS after local therapies are administered, such as radiation and surgical therapies. It is a real unmet need for our patients, and many patients end up dying of their CNS disease over time.

We enrolled 37 patients to the clinical trial and, over the course of the study, 18 women responded to treatment in their CNS, which means that they had a volumetric response in their brain lesions of at least 50%. That was a response rate of 49%, so, nearly half of patients derived benefit from this therapy. 

Why are patients with HER2-positive breast cancer susceptible to getting brain metastases?

We don’t fully understand why HER2-positive disease has a predilection [to spread to] the brain. Some of the hypotheses are that the treatments that we use in the preoperative or postoperative setting do not reach the CNS effectively. So while patients can do well in their system, sometimes the CNS becomes a place that harbors metastases because the treatments that are bulky, such as trastuzumab, do not reach the CNS effectively. 

There has been concerns over increased diarrhea with neratinib. Are the toxicities increased with this combination?

That is a great question. We did see a high rate of diarrhea in patients treated on our study, and it was the most common grade 3 toxicity that we saw. Approximately 32% of patients had grade 3 diarrhea—about 7 stools per day. This is higher than what you would see with past trials of these agents alone. We had all women take preventative doses of loperamide in the first cycle of therapy to try to prevent diarrhea. Despite having that as part of the protocol, we still saw that rate of diarrhea.

What will be the next steps following these findings?

Our results support the ongoing use of an examination of HER2-directed therapy for the treatment of CNS disease. The results are very promising; they show that the combination is active and maybe just as active as local therapy. Future trials are going to be looking at further combinations of agents such as neratinib with chemotherapy, potentially against local therapies. Trying to think of other partners for neratinib is appealing, given the toxicity that we saw. However, capecitabine and neratinib may be a very viable combination to test in the future. 

Is there anything being done to prevent brain metastases before they occur?

Thinking about how to prevent brain metastases is a very interesting question. There haven't been many studies addressing that, and some of it is trying to prevent the toxicity of our treatment before a person even develops their brain metastases. Of course, half of the patients never will. 

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