Expert Discusses Developments in HER2+ Breast Cancer

A. Jo Chien, MD

Novel agents—including pertuzumab (Perjeta), neratinib (Nerlynx), and the investigational agent tucatinib—are rapidly expanding the armamentarium in HER2-positive breast cancer. The key now, explained A. Jo Chien, MD, is optimizing patient selection for these treatments.

“The challenge is finding the right spot for these agents and being able to show meaningful survival benefit,” said Chien. “The goal is maintaining quality of life equal to improving survival.”

OncLive: What is being discussed in early-stage and metastatic HER2+ breast cancer?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Breast Cancer, Chien, associate clinical professor, Department of Medicine, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, discussed emerging agents and other developments in HER2-positive breast cancer.Chien: In the field of HER2-positive breast cancer right now, there are challenges in identifying patients who remain high risk despite trastuzumab.

There are a number of new agents, like pertuzumab and neratinib, that can be used in the early-stage setting. We know that despite trastuzumab, almost one-fourth of patients will relapse and require additional therapies.

Please expand on the emerging agents.

On the flip side, there are patients who we are probably overtreating. Historically, our studies were done in patients with relatively high-risk disease—those with node-positive disease and larger tumors. Now, we are identifying patients with smaller tumors and node-negative disease and finding that maybe they don't need as intensive treatment.In the early-stage setting, that includes pertuzumab, which is an antibody against HER2 that blocks dimerization. We know that it improves pathologic complete response (pCR) rates in the neoadjuvant setting. We have also seen adjuvant data that have shown small benefit. The question is, “Who needs that additional benefit?” There are additional side effects that come along with it, such as diarrhea and rash.

What factors do you take into consideration when deciding on a therapy?

Other agents include small molecule tyrosine kinase inhibitors, such as neratinib, which is also approved in the early-stage setting to be given for 1 year after completing 1 year of trastuzumab. The question is, as they’re both approved in the adjuvant setting, is, “Who needs both?”Pertuzumab is approved in both the neoadjuvant and in the adjuvant setting. We've seen from APHINITY that the benefit is about 1% to 2% in the overall population. However, in the higher-risk patients—those with node-positive and hormone receptor (HR)-negative tumors—the benefit is a little bit larger. Certainly, I would consider adding pertuzumab for those patients.

I don't know that recurrence is the only meaningful endpoint. We know that giving pertuzumab in the neoadjuvant setting can increase pCR, and therefore increase rates of breast conservation. This may minimize axillary surgery. How we manage the axilla is evolving as we're giving more neoadjuvant chemotherapy. Those are meaningful endpoints for patients, as well. Those who were taken to surgery first because they have small amounts of disease probably don't need adjuvant pertuzumab.

What are your thoughts on de-escalation strategies?

Similarly for neratinib, we're seeing the greatest benefit in patients who have higher-risk disease—node-positive with residual disease after neoadjuvant chemotherapy. [This is true] especially in those who have HR-positive disease. Those may be the patients to focus neratinib on.For whom can we decrease the amount of chemotherapy? We started out with our most aggressive regimens, which include anthracyclines. Though the BCIRG-006 study was not powered to look at this, we saw very similar long-term outcomes out to 10 years between non-anthracycline and anthracycline-based chemotherapies. In the APT study in patients with stage I node-negative tumors, we saw great long-term outcomes with disease-free survival rates of 94% at 7 years of follow-up.

Also, who needs the full 1 year of trastuzumab? That was chosen arbitrarily. We know that patients do not benefit for longer than 1 year. We've seen data showing that less than 12 months can be equally beneficial. Those are the 2 current strategies with data.

Has your practice changed following the PERSEPHONE trial data?

There are other ones being explored, such as giving just hormone therapy with either trastuzumab or a small molecule TKI. A subset of those patients will achieve complete responses without chemotherapy. All of those are strategies being explored.The PERSEPHONE trial looked at 6 months versus 12 months of adjuvant trastuzumab. It was designed to allow for 3% difference between the 2 groups. We have to ask whether that is valuable and meaningful to patients. Certainly, we approve drugs with a 3% difference, such as neratinib and pertuzumab.

How does the ExteNET trial play into this?

I don't know that we can say, “6 months is okay for everybody.” It's definitely not considered the standard of care. Having said that, when you look at this 4000-patient trial, which is really the largest trial of the ones we've seen, the number of events at 4 years is very similar. This means that there is a large subset of patients who probably will be okay with less [treatment]. It's something to be considered in our lower-risk patients and in those with cardiac risk factors.The ExteNET trial asked whether we can further improve long-term outcomes in patients after 1 year of trastuzumab. They randomized patients to a year of neratinib versus placebo and found that the benefit was small in the overall population; it was about 1% to 2%. In the HR-positive population that benefit was larger; it was about 4% to 5% at 5 years.

There was grade 3 diarrhea in the initial study—so very high rates; about 40% of patients had grade 3 diarrhea. We're finding that with prophylactic use of an antidiarrheal, we can reduce the rate of diarrhea to make it a tolerable regimen. There is a place for neratinib in the early-stage setting for HER2-positive early-stage breast cancer. It's defining who needs it based on clinical factors. There is [also] a place for molecular subtyping.

In metastatic disease, how have antibody-drug conjugates (ADCs) impacted the landscape?

Are there any updates with tucatinib?

We have done well in early-stage HER2-positive breast cancer. Without trastuzumab, the prognosis is poor and more aggressive than HER2-negative disease. We are curing the majority of patients by far. It's pretty remarkable that in a relatively short amount of time, we are now swinging the other way to find ways to give patients less treatment. The challenge is how to do that safely and for whom.The first one to be approved was ado-trastuzumab emtansine (T-DM1; Kadcyla). It is currently approved primarily in the second-line setting after trastuzumab and pertuzumab. Recently DS-8201 was presented. It is another ADC that has shown some impressive responses in the phase I setting in not only HER2-positive disease, but also HER2-low and HER2-negative breast and gastric cancers. We're excited about that drug. It's currently in phase II and phase III trials; we'll hear a lot more about it.Many, if not all of the tyrosine kinase inhibitors (TKIs), have the potential to penetrate the blood-brain barrier. Many have been looked at extensively, including lapatinib (Tykerb) and neratinib. As single agents, we haven't seen compelling data in terms of responses. However, we have seen pretty impressive responses in the central nervous system in combination with capecitabine.

What else is being discussed in the metastatic setting?

What does the future hold?

Tucatinib has also shown that, as well as long durations of response in combination with trastuzumab and capecitabine. These are patients who also are heavily pretreated. The unique thing about tucatinib is that it has more preferential binding to HER2 than EGFR, and therefore has lower rates of diarrhea. The gastrointestinal toxicity has really been an “Achilles heel” for this class of agents in particular. Tucatinib's safety profile from that regard looks promising. If we can find a TKI that is tolerable and also penetrates the blood-brain barrier, it will meet a very large and unmet need.There is a lot of talk about how well HER2-positive patients do in the metastatic setting. Certainly, we are seeing some long-term survivors with metastatic disease and patients who have no evidence of disease after first-line chemotherapy, trastuzumab, and pertuzumab. The challenge is that the bar is high for drug development in this space. In this space, toxicity profile is equally important as these patients are living a long time and doing very well.The ADCs that we discussed [are part of the future]. There are a number of TKIs in development with different safety profiles. How they do in their toxicity profile will play an important role in their success. There is a lot of interest in combining immunotherapies with trastuzumab and other HER2-targeted agents; there are trials combining PD-1/PD-L1 agents. Those look very interesting. We've seen response rates of about 15% with single-agent immunotherapy. We're also looking at CDK4/6 inhibitors in the HER2-positive space as well. There are a lot of interesting agents coming down the pike. The challenge is figuring out who needs what.