Expert Recaps Adjuvant Advancements in HER2+ Breast Cancer

Haythem Y. Ali, MD

The 2 biggest advancements in the treatment of patients with HER2-positive breast cancer in the last year were FDA approvals in the adjuvant setting, according to Haythem Y. Ali, MD.

In July 2017, the FDA approved neratinib (Nerlynx) for the extended adjuvant treatment of patients with early-stage, HER2-positive breast cancer following postoperative trastuzumab (Herceptin). This approval was based on data from the phase III ExteNET trial and the phase II CONTROL trial.

Later that year in December, the FDA approved pertuzumab (Perjeta) in combination with trastuzumab and chemotherapy as an adjuvant treatment for patients with HER2-positive early breast cancer at high risk for recurrence. Findings from the APHINITY trial, which led to the approval, showed that treatment with pertuzumab, trastuzumab, and chemotherapy demonstrated a 3-year invasive disease-free survival rate of 94.1% versus 93.2% for those who received trastuzumab plus chemotherapy and placebo (HR, 0.82; 95% CI, 0.67-1.00; P = .047).

Although both of these regimens have been FDA approved, they are not appropriate for every patient with HER2-positive breast cancer, Ali said. Either neratinib or pertuzumab with trastuzumab as adjuvant treatment will be most optimally used in patients with high-risk disease, he explained.

OncLive: What have been some of the most notable recent advances in HER2-positive breast cancer?

How do you choose between the 2 strategies?

Ali, a senior medical oncologist at Henry Ford Hospital, discussed how the landscape of HER2-positive breast cancer has evolved in the last decade during a presentation at the 2018 OncLive^® State of the Science Summit™ on Breast Cancer. In an interview during the meeting, Ali discussed adjuvant advances in HER2-postitive breast cancer and emerging agents in the field.Ali: In the HER2 sphere, the 2 big pieces of news were the dual-antibody therapy with trastuzumab and pertuzumab, and then the other piece of news is the adjuvant therapy approval for neratinib. Neratinib was given in patients who had never received dual-antibody therapy. There were slight differences in the subgroups regarding benefit. Instead of throwing everything at everybody, my goal [for the presentation] was to try and figure out how to choose the best treatment for the right person.Both are dose-escalation strategies. You want to make sure to first target the patients who will benefit the most. The amount of benefit from each of these strategies is small when you add in lots of patients. However, if you focus on the higher-risk patients, these small increments mean a lot more. The first thing to do is make sure that you are targeting these types of treatments to high-risk patients. The question is, “Which high-risk treatments receive which escalation?” Thankfully, we have a good subgroup analysis in each of these trials, which may help us make those decisions. We just need to be aware of them so we can make the right decisions.

In terms of the dual-antibody therapy, it looks like the group that seems to have benefitted the most were patients with hormone receptor (HR)—negative status and those who had lymph node–positive status. We want to target this group with the dual-antibody therapy.

In terms of what is coming down the pike, what other adjuvant strategies are being investigated?

The nice thing about the neratinib trial is that it was done in patients who didn't get pertuzumab, and it is showing a benefit in the estrogen receptor—positive group. If you have a patient who has HR-positive disease and you don’t want to add in pertuzumab but they are high risk, you may want to escalate by giving them adjuvant neratinib. On the other hand, the ones who have HR-negative disease—who did not seem to benefit from the neratinib trial—are perhaps those who you want to choose a dual-antibody strategy for. This is my way of looking at the data; it is not a national standard. I am trying to use the data to the best of my ability to treat patients right now until we get more information. In the past, we have looked at lengthening the time of trastuzumab, which didn't seem to work. However, a strong adjuvant strategy right now is de-escalating to single chemotherapy with trastuzumab. That is going to gain more momentum in the future.

There are newer adjuvant therapies, such as T-DM1, and we will be looking to see how that will work. The area that T-DM1 will likely be useful is in the patients who don't achieve a complete response in the neoadjuvant setting. There are trials ongoing in that sphere, which may be helpful.

What TKIs are being considered?

Are there any other emerging agents?

What are your thoughts on immunotherapy for HER2-positive patients?

HER2-positive breast cancer used to be one of the worst prognoses for breast cancer, but now the outlook for these patients is much better. How is the field progressing?

In the metastatic setting, there are other tyrosine kinase inhibitors (TKIs) that are more selective than neratinib and may have less adverse events (AEs). If those succeed, maybe they can be used in the adjuvant setting. There is tucatinib, which is a selective anti-HER2 TKI. It is associated with less AEs than the TKIs that we have right now, at least from the information available. There is a phase III trial ongoing, so hopefully we will get those results and see how that works. There are a couple of [antibody-drug conjugates] that are coming down the pike. The one that we currently have, T-DM1, is a conjugate of trastuzumab plus emtansine. We can actually use the same backbone of trastuzumab and keep changing the chemotherapy delivery, and we end up with different drugs. We started getting smarter with this—not just by choosing medications that work differently than emtansine, but also increasing the drug-to-antibody ratio—how many drug molecules are attached to each antibody. By increasing the drug-to-antibody ratio, you actually deliver more drug into the cancer cell. Right now, most of the data with immunotherapy seem to be with patients who have triple-negative breast cancer. I don't see why there should not be a role for it in HER2-positive patients. There was a trial presented at the 2017 San Antonio Breast Cancer Symposium that looked at immunotherapy in HER2-positive breast cancer. I definitely think it will have a role in the future. How much of a role? We don't know that.As oncology professionals, we have to think about HER2-positive breast cancer with treatment and without treatment. I do agree that with treatment, the prognosis is very good. If you let it be, it reverts right back to its bad habits. We have not changed the nature of HER2 disease, but we have changed prognosis through intervention. Tumors that are triple-positive actually have the lowest stage in the clinical prognostic staging, and triple-negative tumors have the highest stage. However, if you went by the TNM staging system, they would be basically equivalent tumors. With treatment, we have changed the prognosis to a better one, which is an important thing.

von Minckwitz G, Procter MJ, De Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377:122-131. doi: 10.1056/NEJMoa1703643.