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Adjuvant Treatment Evolving for HER2+ Breast Cancer

Angelica Welch
Published: Monday, Nov 27, 2017

Using neratinib in the adjuvant setting is reasonable in patients who are at high risk, such as those who have node-positive disease and, given the subgroup analysis, patients who have HR-positive disease. It is important to realize that the ExteNET population is a pertuzumab-naïve population, so it shouldn't be used in patients who have previously received pertuzumab.

What should physicians take into consideration if they decide to take this route? 

It is hard because APHINITY is a positive study that showed benefit, but the benefit was small. Honestly, the financial cost is high. Pertuzumab costs $100,000 and, when they calculated the number for the amount that you would need to prevent just 1 recurrence, it comes out at $5.6 million. Therefore, the costs for society, if we started adapting and using pertuzumab in all of our stage II/III HER2-positive patients, is enormous. We need to figure out which patients need pertuzumab, so the biomarker work that will come out of APHINITY will be very important. For now, given the data that we do have, picking those patients who are thought to be at highest risk is probably the way to go. 

What studies are investigating neratinib in combination? 

In the metastatic setting, there is a trial that compared capecitabine and lapatinib (Tykerb) to capecitabine and neratinib. Certainly, one would think that a potential problem with this combination would be a lot of diarrhea, given that both agents by themselves can give a lot of diarrhea. However, this trial did institute an Imodium prophylaxis throughout, so it was tolerable. We are awaiting the results of that trial, and that will be interesting. 

There is also an ongoing study combining neratinib with hormonal therapy in the metastatic setting. Given the subgroup analysis that we saw from ExteNET, suggesting that the majority of benefit was in the ER-positive population, this trial is randomizing metastatic HR-positive/HER2-positive patients to either neratinib and fulvestrant (Faslodex) or neratinib alone. This is to tease out whether this activity may be from synergistic activity with hormonal therapy. That will be interesting to see. 

Anecdotally, how have you seen the approval of neratinib impact clinical practice?

I had treated a lot of patients on the ExteNET trial, and the diarrhea that occurred tended to occur early. Therefore, [use it] if you can manage it; we have since learned how to use Imodium to prevent diarrhea. You have to keep in mind that these are patients who are in the adjuvant setting and they have already completed 1 year of chemotherapy and trastuzumab. It is a long road to go through another year of HER2-directed therapy, particularly an agent that is associated with diarrhea, requires management of toxicity, and sometimes [requires] dose modification. It is a lot to put a patient through, so we have to be mindful about selecting which patients need such extended treatment. 

Are there any other novel HER-targeted agents in the pipeline?

One interesting novel HER2 agent is tucatinib (ONT-380). That agent targets HER2, but it does not seem to have the toxicity that we see with lapatinib, where you also hit EGFR and patients get rash and diarrhea. Therefore, it’s a potent HER2 inhibitor, but without the diarrhea toxicity. That agent looks very promising; it also has CNS penetration. There is a randomized trial, the HER2CLIMB study, which is currently enrolling patients who have metastatic HER2-positive disease. The trial is randomizing these patients to capecitabine and trastuzumab, or capecitabine, trastuzumab, and tucatinib. We will see; it is an exciting drug. 

Looking toward the future, how is the treatment of HER2-positive breast cancer progressing?

There are a lot of interesting drugs being tested, particularly right now in the metastatic setting. Two additional areas that will possibly change the future of management are immunotherapy and CDK 4/6 inhibition. We will see data at the 2017 San Antonio Breast Cancer Symposium from the PANACEA trial, which looked at the combination of pembrolizumab (Keytruda) and trastuzumab in patients who have metastatic HER2-positive disease. There has also been a bunch of data that have been done looking at CDK 4/6 inhibition in HER2-positive disease. Some early preclinical work has suggested that trastuzumab-resistant patients may particularly be sensitive to CDK 4/6 inhibition. Currently, there is an ongoing randomized trial—the monarcHER trial—which is looking at abemaciclib (Verzenio) in the trastuzumab-resistant population, and comparing with physicians-choice chemotherapy. That trial should, hopefully, complete accrual early next year, so we will see.

View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
34th Annual Miami Breast Cancer Conference® Clinical Case Vignette Series™May 25, 20182.0
Community Practice Connections™: CDK4/6 Inhibitors With the Experts: The Role of Emerging Agents for the Management of Metastatic Breast CancerMay 30, 20182.0
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