New Agents, Approaches Finding Place in Neoadjuvant HER2+ Breast Cancer

Sara A. Hurvitz, MD

With 3 neoadjuvant therapy regimens available for patients with HER2-positive breast cancer, researchers are still investigating other agents and regimens in this setting to improve outcomes.

For example, the ADAPT study examined 5000 patients with various breast cancer phenotypes.¹ In HER2-positive patients (n = 376), ado-trastuzumab emtansine (T-DM1; Kadcyla) with or without endocrine therapy demonstrated a benefit, versus trastuzumab with or without endocrine therapy.

The pathologic complete response (pCR) rate was found to be substantially higher in the T-DM1 arms compared with trastuzumab plus endocrine therapy (P <.001). In the T-DM1—alone arm (n = 37), the pCR rate was 40.5%. In the arm with T-DM1 plus endocrine therapy (n = 48), the pCR rate was 45.8%. In the arm with trastuzumab (Herceptin) plus endocrine therapy (n = 45), the pCR rate was 6.7%.

Additionally, the randomized multicenter neoadjuvant KRISTINE trial² is examining T-DM1 plus pertuzumab (Perjeta) versus chemotherapy plus trastuzumab and pertuzumab in patients with HER2-positive disease. Results of this study will be presented in June at the 2016 ASCO Annual Meeting.

OncLive: How far have we come in terms of neoadjuvant options and their efficacy in HER2-positive breast cancer?

In an interview with OncLive, Sara Hurvitz, MD, medical oncologist, General Internal Medicine, Hematology and Oncology at UCLA, discusses ongoing neoadjuvant studies in HER2-positive breast cancer, as well as what the future holds for neoadjuvant therapy.Hurvitz: Currently in the United States, the FDA has approved 3 neoadjuvant regimens. They approved them based on 2 small phase II clinical trials: the NeoSphere study and the TRYPHAENA study. The NeoSphere study investigated giving 4 cycles of docetaxel (Taxotere) plus trastuzumab and pertuzumab followed by surgery. Then, after surgery, they receive 3 cycles of FEC—anthracycline-based chemotherapy. That is 1 of the regimens that was FDA approved based on very nice pCR data and encouraging event-free survival data.

In the 3-arm TRYPHAENA study, all patients received both trastuzumab and pertuzumab. There were only 225 patients enrolled in that study, and they compared the TCH regimen (docetaxel, carboplatin, and trastuzumab) plus trastuzumab in 1 arm for 6 cycles followed by surgery, versus FEC followed by THP (docetaxel, trastuzumab, and pertuzumab), versus pertuzumab, trastuzumab, docetaxel, and carboplatin. Therefore, that third arm combined a concurrent anthracycline with the dual HER2-targeted therapy.

The primary endpoint of that study was cardiac safety, and there was no difference in grade 3/4 cardiac events, even with concurrent administration of epirubicin with dual HER2-targeted therapy. Because the study was small and didn’t have long-term follow-up, the FDA did not believe it was enough data to approve that regimen.

However, the other 2 arms were approved for neoadjuvant therapy, so that is the standard. At UCLA, we use TCHP (trastuzumab, carboplatin, docetaxel, and pertuzumab) and the pCR rates are very high—above 50% in patients who receive it. Plus, they don’t have to have chemotherapy after surgery.

There are also some data coming out with abemaciclib in the neoMONARCH trial for patients with HER2-negative disease. Is this being studied in HER2-positive patients?

Also, all chemotherapy is given concurrently with HER2-targeted therapies and then, after surgery, patients receive single-agent trastuzumab as maintenance therapy. If their tumor is HR-positive, we add in endocrine therapy.There is a study that is about to get started, or has just started, that is looking at HR-positive/HER2-positive metastatic breast cancer. Our own cell line data on CDK 4/6 inhibitors in breast cancer shows that not only luminal ER-positive/HR-positive breast cancer cell lines are sensitive to CDK 4/6 inhibition but, indeed, a number of HER2-positive lines are sensitive, as well.

What are some neoadjuvant trials that you are excited about?

Abemaciclib has a different safety profile than other CDK 4/6 inhibitors, so it is also going to be interesting to see how that plays out in a larger patient population in these larger, ongoing studies that are going to be presented in the next 6 to 12 months.The ADAPT study presented by Dr Nadia Harbeck is very exciting. It is looking at the use of T-DM1 in ER-positive/HER2-positive breast cancer. Here, pCR rates are 45% with T-DM1, which was much higher than patients who received trastuzumab plus endocrine therapy. That is very encouraging data.

What work would you like to see done in this field?

At the 2016 ASCO Annual Meeting, we will present the results of the KRISTINE trial, which is a phase III 2-arm randomized clinical trial comparing TCHP for 6 cycles prior to surgery versus T-DM1 plus pertuzumab for 6 cycles prior to surgery.We’re really beginning to appreciate the fact that HR-positive/HER2-positive breast cancer behaves quite differently. It has different surgical and long-term outcomes compared with HR-negative/HER2-positive breast cancer. We are also beginning to see a difference in outcomes with PI3K pathway activation status, so that may help inform decision-making and make treatment options available in the future.

How do these patients have different surgical and long-term outcomes?

Then, looking at CDK 4/6 inhibition in HER2-positive breast cancer is going to be really important because the therapeutic index of CDK 4/6 inhibitors is actually quite good when you compare it with other therapies. We need to look at combining them with the HER2-targeted therapies and even endocrine therapies in that realm.When there is HR overexpression with HER2 expression, we see much lower rates of pCR at the time of surgery. However, what we aren’t seeing is that pCR predicts long-term outcomes.

In other words, if a woman goes through neoadjuvant chemotherapy and HER2-targeted therapy and does not achieve a pCR, that doesn’t necessarily predict a poorer outcome. These patients are going to be getting at least 5 years of endocrine therapy, as well. The tumors regress more slowly, so that’s sort of the initial response we see at the time of surgery.

What do you envision as the future treatment landscape of HER2-positive disease?

In contrast, for HR-negative/HER2-positive patients, pCR does seem to be fairly predictive of long-term outcomes.Subsetting out HER2-positive breast cancer is going to be the wave of the future because there are HER2-positive breast cancers that do not respond to targeted therapies. Something else is molecularly driving these cancers. It may not be expression or amplification in these tumors. Understanding how to better treat each of these subtypes, and whether or not we can use molecular profiling to predict whether or not a cancer will respond to a given therapy is going to be the way forward.

These therapies are very exciting, but they are also very expensive. In the current health economic situation that the world finds itself in, it is going to be important for us to define, early on, which tumors are most likely to respond to these therapies, so that we don’t waste time and resources treating patients all as one disease and doing trial and error.

This understanding is going to come from doing more tissue acquisition studies. In the metastatic setting, it is critical that we get fresh biopsies from patients and not rely on archived tumor samples.

1. Harbeck N, Gluz O, Christgen M, et al. Efficacy of 12-weeks of neoadjuvant T-DM1 with or without endocrine therapy in HER2-positive hormone-receptor-positive early breast cancer: WSG-ADAPT HER2+/HR+ phase II trial. J Clin Oncol. 2015;33 (suppl; abstr 506).
2. NIH Clinical Trails Registry. www.ClinicalTrials.gov. Identifier: NCT02131064.