I-SPY 2 Paves the Way for Novel HER2-Targeted Agents in Breast Cancer

Debu Tripathy, MD

There are a wide variety of novel agents currently being investigated in the neoadjuvant setting for patients with HER2-positive breast cancer.

The I-SPY 2 trial—which is designed to compare the efficacy of several novel drugs in combination with chemotherapy with the efficacy of standard therapy alone—is investigating the allosteric AKT inhibitor MK-2206, the tyrosine kinase inhibitor neratinib, and the immune checkpoint inhibitor pembrolizumab (Keytruda) in neoadjuvant HER2-positive disease.

“There is a lot of activity going on in the HER2 space,” explains Debu Tripathy, MD.

OncLive: Are there agents in the neoadjuvant HER2-postive setting that you are particularly excited about right now?

In an interview with OncLive, Tripathy, who is chair of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, discussed the potential for these agents and what is ahead for the I-SPY 2 trial.Tripathy: There is 1 drug, neratinib, which was tested in the I-SPY 2 trial that interestingly showed a benefit in the triple-negative group, suggesting that there may be a group of triple-negative patients that still signals through HER2.

There is another drug called MK-2206, which is an AKT inhibitor, that, when added to trastuzumab (Herceptin), improved the pathologic complete response rate (pCR).

What is the mechanism of action for MK-2206?

There are also ongoing trials that are proposing immunotherapy and looking at the addition of checkpoint inhibitors to see if 1 can improve the pCR. Some of the newer drugs being used in the metastatic setting will eventually make their way into the neoadjuvant setting, as well.MK-2206 is an AKT inhibitor and it is part of the signaling pathway that most growth-factor receptors use. PI3 kinase, AKT, and mTOR are all enzymatic steps that ultimately lead to the induction of the cell cycle. The problem is that many growth factors use them so they are not specific, but it is also a good thing in that many growth factors use them. It is a convergence; it is sort of the “Grand Central Station” of cell signaling.

AKT is a little bit different. It is not a small molecule inhibitor like a lot of the other kinase inhibitors; it is an allosteric inhibitor and it seems to work particularly well. There are other drugs that tend to only work when AKT is mutated, similar to more traditional TKIs. The rate of AKT mutation is actually quite low—in breast cancer it is probably only 1% to 3%. However, the allosteric inhibitor may only work when normal signaling is going through the nonmutated AKT. It still too early to tell and we will need more studies in this area.

Are there going to be more additions to the I-SPY 2 trial for HER2-positive disease?

What potential could immunotherapy have in HER2-positive breast cancer?

Unfortunately, before MK-2206 got to the I-SPY 2 program, it was a drug that was not going to be carried further by the drug company. The success in I-SPY 2 was a bit unexpected. Where that drug is going to go is a little bit up in the air right now.Yes, there are going to be more additions to the targeted drugs in I-SPY 2. There are some newer HER2-specific kinase inhibitors that will be looked at. Immunotherapy, specifically pembrolizumab, will come into the mix and has already started.There clearly is potential in that HER2-positive cancers are immunogenic enough that we can use immunotherapy. There is evidence of this from the original adjuvant HER2-positive breast cancer trials—where a small subset of patients had immune infiltrate and a lot of lymphocytes in the tumor, so we know they were more immunogenic. These patients seemed to do better even without trastuzumab, suggesting that maybe there is a natural immunity that chemotherapy alone can help with.

Also, there is some thinking that perhaps trastuzumab and pertuzumab (Perjeta), in addition to blocking HER2 signaling, are actually activating the immune system. They do have the ability to recruit T cells and activate antibody-dependent cellular cytotoxicity.

Therefore, it is possible that part of the reason why trastuzumab and pertuzumab have such a profound impact on survival is due to an immune effect. Immune effects are persistent, so that could also explain why we have seen these very long responses in a few patients with metastatic HER2-positive disease. All of us who are in practice have patients who have survived 10 to 15 years, and it is probably because of an immune effect.