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Rachel A. Freedman, MD, discusses treating patients with HER2-positive breast cancer who develop CNS metastases, and the promise that neratinib holds in this patient population.
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.
A phase II trial is currently evaluating the effect of neratinib (Nerlynx) plus capecitabine in patients with HER2-positive breast cancer who have developed CNS metastases. Findings presented at the 2017 ASCO Annual Meeting suggest that the combination of neratinib and capecitabine is active, supporting further development of the regimen. Specifically, out of 39 enrolled patients, 49% had a volumetric sum of target CNS lesions (95% CI 32-66, neurologic exams not yet available on all pts). Additionally, the overall 12-month survival rate was 63% (95% CI, 43-77).
Neratinib was approved by the FDA this past July for the extended adjuvant treatment of patients with early stage, HER2-positive breast cancer following postoperative treatment with trastuzumab (Herceptin).
In an interview with OncLive, 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.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.
Therefore, we conducted a trial that used neratinib, which is an oral anti-HER2 agent, and combined it with capecitabine, a chemotherapy agent shown to be effective in the HER2-positive breast cancer setting. We gave this to women who have CNS metastases from their HER2-positive breast cancer after having progressed on any prior local treatment to their brain whether it was radiation, surgery, or any combination.
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. 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. 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.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. 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.
We must do better at trying to predict who those patients are going to be—who are going to develop CNS metastases and then target them in a preventative clinical trial. Otherwise, a lot of these combinations in the brain, such as neratinib and capecitabine, are also active systemically, so there may be a clinical trial that one could do.
The NALA trial is looking at this combination we used in our trial against lapatinib (Tykerb) and capecitabine in women without CNS disease. If it does show superiority, then that may be a potentially active systemic therapy that will hopefully prevent brain metastases. We don't know the answers to these questions, and they all need to be addressed in future studies. Targeting dual anti-HER2 therapy is very appealing and may limit the side effects that you see, particularly if you use an agent like ONT-380, which doesn't have as much of a spillover effect and maybe less diarrhea than some of the other agents, such as lapatinib or neratinib. In our program, we are definitely looking at these combinations of dual HER2 therapy. In fact, ONT-380 is being looked at in combination with trastuzumab as dual HER2 combination therapy, and there are signs of activity. That is the future and maybe next steps. [They should just be] aware that there are a lot of clinical trials in this space right now for CNS disease, particularly in the HER2-positive space. For patients who are progressive after having some sort of standard local therapy, I would encourage local doctors to look around and see what clinical trials are available, because this is the perfect space to treat patients such as these. Reaching for the agents that are available to you makes sense, and of course, resist your local therapy options. I do hope that someday soon all our data will turn into approved regimens that will be available to all oncologists.
Freedman RA, Gelman RS, Melisko ME, et al. TBCRC 022: Phase II trial of neratinib + capecitabine for patients (Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases (BCBM). J Clin Oncol. 2017;35(suppl; abstr 1005).
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