Efforts Continue to Refine Neoadjuvant HER2+ Breast Cancer Care

Douglas Yee, MD

Since the 2013 FDA approval of a neoadjuvant pertuzumab (Perjeta) for patients with HER2-positive breast cancer, researchers have continued to explore novel agents in the setting, including T-DM1 (Kadcyla) and neratinib.

Despite these efforts, slightly more than half of patients still will not have a pathological complete response (pCR) in the neoadjuvant setting using best available therapies, said Douglas Yee, MD, professor of Medicine and Pharmacology, medical oncologist, University of Minnesota Medical School.

In an interview with OncLive, Yee explains current treatment options and ongoing research aimed at optimizing neoadjuvant therapy for HER2-positive breast cancer.

OncLive: What is the standard treatment for HER2-positive breast cancer in the neoadjuvant setting?

Dr Yee: Right now, the standard treatment for patients with large breast cancers that are greater than 2.5 cm is neoadjuvant therapy with trastuzumab, pertuzumab, and a taxane-based regimen. The demonstration that this combination increases pathological response rates is fairly strong and led to an accelerated approval by the FDA of that combination in 2013, based on the phase II NeoSphere trial.

The trial compared docetaxel with trastuzumab or the triplet of docetaxel, trastuzumab, and pertuzumab. In that trial, the pCR was statistically increased. It was a relatively small trial with approximately 400 patients in total. That data, along with the FDA’s meta-analysis of the value of pCR, led to the accelerated approval.

Pertuzumab was approved with a boxed warning. What are the toxicity concerns with the drug and have these been manageable?

We see diarrhea with it, as well as count suppression, both platelets and white counts. I think they have been pretty manageable. Certainly in the neoadjuvant setting, where we see people frequently, these toxicities are fairly manageable. If pertuzumab extends into the year of anti¬—HER2-based therapy, we will have to pay attention more closely. We tend not to follow women as closely in the year of antibody therapy, but we do need to pay attention to the counts. Overall, pertuzumab is extremely well tolerated.

Results from the phase II ADAPT trial presented at the 2015 ASCO Annual Meeting showed promise for chemotherapy-free neoadjuvant treatment with T-DM1 in patients with HER2-positive and HR-positive early breast cancer. Can you discuss these results?

T-DM1 is a very interesting molecule. It is trastuzumab chemically linked to a chemotherapy drug. That clinical trial evaluated the triple-positive subgroup of women—those who are ER-positive, HR-positive, and HER2-positive. The endpoint was pCR.

The pCR rate was very high for T-DM1, a little bit higher when endocrine therapy was added, and [much lower] for trastuzumab plus endocrine therapy. Therefore, the evidence that T-DM1 is a very active agent in the neoadjuvant setting was shown by that study.

What are the next steps with research in the neoadjuvant HER2-positive setting?

We will have to examine which patients do not do well with trastuzumab-based therapy. If you look in the neoadjuvant setting, slightly more than half of patients will have a pCR, even with our best therapies. We are going to have to look at the molecular features of these therapies to identify the women who do not do well with them, even though they have the HER2 target.

There have been some clues, including the mutation in PI3 kinase catalytic domain, which may predict resistance to trastuzumab-based therapies. If that is true, it must be tested to determine if the inhibitors that block PI3 kinase signaling will have a role in treating these women. To me, that is also relevant in the neoadjuvant setting because it is easier to obtain tissue and it is easier to do these types of analyses that look very specifically at mutations and then link them to a very definable endpoint that can be achieved in 12 to 24 weeks, as opposed to 2 to 5 weeks for a “regular” adjuvant therapy.

Are there ongoing studies in this area?

I have been involved with the I-SPY 2 clinical trial. One of the drugs we first put into that trial was the tyrosine kinase inhibitor TKI neratinib. When the trial was formed, the arms were neratinib with trastuzumab and trastuzumab with paclitaxel. The neratinib and trastuzumab arm was superior. That is now being tested in a larger randomized phase III trial to see if the TKI has a place. The biggest challenge is that, since we did the trial, pertuzumab came along. Now, the control arm changes and we have to rethink the trial design.

Are there other investigational agents that have shown promise in the neoadjuvant HER2-positive setting?

At ASCO this year, the I-SPY 2 group presented data for an AKT-inhibitor MK-2206. In the trial, MK-2206 was superior to trastuzumab and a taxane in HER2-positive subgroup patients, as well as in triple-negative patients.

When we think about targeting the HER2-molecule, to date almost all of our therapies have been directed at the receptor itself. The antibodies bind to the outside of the receptor and the TKIs limit the biochemical function of the receptor. We know that receptor triggers a lot of downstream signaling molecules. Whether you can target that in conjunction needs to be tested. We are seeing more and more drugs enter that are signal transduction inhibitors, and understanding how they can combine with trastuzumab or pertuzumab is where we need to go.