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

Gina Columbus @ginacolumbusonc
Published: Tuesday, Apr 26, 2016

Sara A. Hurvitz, MD

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.

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.

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

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.

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 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?

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.

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.

What are some neoadjuvant trials that you are excited about?

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.


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