Novel Therapies in Development for HER2-Amplified Breast Cancer

Sherene Loi, MD, PhD

As part of our coverage of the American Society of Clinical Oncology (ASCO) Annual Meeting, we are joined by Sherene Loi, MD, PhD, a medical oncologist who conducts immune- and genomics-based breast cancer research and who heads the Translational Breast Cancer Genomics and Therapeutics Laboratory at the Peter MacCallum Cancer Centre in Melbourne. At the meeting, Dr. Loi provided an overview of some of the novel therapeutics that are in development for HER2-amplified breast cancer.

-Interviewed by Anna Azvolinsky 

Cancer Network: Dr. Loi, what have we learned about the biology of HER2-amplified tumors in the years since the development of monoclonal antibodies against HER2, such as trastuzumab and pertuzumab, and the oral inhibitors that target HER2 and HER1, such as lapatinib?

Dr. Loi: In the last 10 or 11 years since the report on adjuvant trastuzumab and its efficacy, we have learned that HER2 is an important driver in breast cancer and that trastuzumab and chemotherapy have significantly changed the natural history of HER2-positive disease. Recent data from the original HERA study showed that the effect of trastuzumab still persists 11 years later, even in the many patients who crossed over from the control arm to trastuzumab. Since the development of trastuzumab, we have tried to improve: we’ve done double HER2 targeting in two studies that used lapatinib, afatinib, and neratinib, as well as other monoclonal antibodies such as pertuzumab. I think what we have learned is that double HER2 blockade is only needed in some types of HER2-positive breast cancer, and challenges for the future will be to understand who those patients are. I believe it is likely that patients with estrogen receptor (ER)-negative, HER2-positive breast cancers will benefit most from the double anti-HER2 strategy.

We’ve also learned that targeting the immune system is important in this type of breast cancer. The most likely reason that trastuzumab has been so effective is because it not only targets HER2, but it also enhances the host antitumor immune response. Some would say that the adjuvant APHINITY data were quite disappointing in that the absolute benefit of the addition of pertuzumab was quite small. However, there was a significant 20% relative risk reduction with the addition of pertuzumab, and for some patients that relative reduction will be very important. I am particularly thinking of those patients with high tumor burden or a high number of positive lymph nodes at diagnosis. In data published in the New England Journal of Medicine, the double anti-HER2 strategy was most beneficial in ER-negative and node-positive disease. What we also learned from the APHINITY data is that node-negative, HER2-positive breast cancer patients are doing very well at the moment with just trastuzumab and chemotherapy-these patients should now be considered to have highly curable disease.

The other thing that we have neglected and that has come to the forefront in the last year or so is the estrogen signaling component. About half of HER2-positive breast cancers also express the ER. I think we have forgotten about that pathway until recently, and there are some new drugs that are in development that may target patients with HER2-positive, ER-positive disease. The recent adjuvant neratinib data from the ExteNet trial suggests that neratinib after 1 year of trastuzumab may be of benefit in HER2-positive, ER-positive patients. This could be due to the pattern of relapse being different from ER-negative disease

I think we need to be a bit cleverer in how we develop drugs in the HER2 space in the future. Rather than investigating everyone in the early-stage setting, we need to focus on patients with large tumor burden and a high number of positive lymph nodes. For now, the majority of patients with advanced HER2-positive disease present with stage IV disease, so we need to focus our efforts on these patients-on how to prolong survival or even cure them. In the early-stage setting, we may be focusing in the future on de-escalation efforts-ie, can we get away with less chemotherapy? This is where pertuzumab may be of most interest for the majority of patients.

Cancer Network: What are some of the novel therapeutics that are now in clinical development for HER2-positive breast cancer? Are there drugs that are not directly targeting HER2 amplification but are still relevant for HER2-positive disease?

Dr. Loi: As a general concept, for patients who are incurable with advanced-stage HER2-positive breast cancer, I think that most of the drugs in development are focusing on more potent HER2 signaling inhibition, as well as specific clinical scenarios like brain metastases. Often now you get good control of the cancer outside of the brain but have metastases continuing to grow in the brain or central nervous system (CNS). There is a new tyrosine kinase inhibitor called tucatinib, previously known as ONT-380, which is currently in a large phase II/III randomized trial looking specifically at the question of whether these drugs can treat CNS metastases. There are other drugs that show promise in this area; there were data presented at the ASCO meeting on neratinib and capecitabine having an excellent response rate just in the brain.

They are also trying to enhance immune activation associated with trastuzumab-as well as targeting HER2-using other types of novel therapeutics such as a drug called margetuximab, which is an Fc-optimized monoclonal antibody. And there are drugs that target the cell cycle pathway, such as the CDK4/6 inhibitors, currently in development for HER2-positive disease; there have been a lot of preclinical data that this pathway is very relevant for HER2-positive disease as well as ER-positive/HER2-negative breast cancers. There are many antibody-drug conjugates also currently in development. These are similar to trastuzumab emtansine, that is, they deliver chemotherapy right to where they target HER2, so presumably targeting the cancer cell and sparing the normal cells. I will note, however, that the leader in the field, MM-302, was recently deemed futile in the randomized phase II HERMIONE trial.

Cancer Network: Are there any types of trials with these or other agents in development that you would like to see that you have not yet seen in the clinic?

Dr. Loi: After seeing the pertuzumab data, I think we need to focus trials on the patients who don’t have immune activation against the tumor or who have lower levels of HER2, who may present with high tumor burden or aggressive disease, since we can’t seem to make an impact on their survival-probably because we don’t understand much about their biology. These are the patients that are treated with neoadjuvant anti-HER2 therapy and chemotherapy and have a large amount of residual disease remaining. In general, I think that we are moving toward combinations of HER2-targeting and specific immune-targeting agents, as well as working on drugs that can act against CNS involvement, because that is often what patients die of in the advanced-disease setting. The future is to try to understand more about the biology of resistant disease, novel combinations, immunotherapy and dealing with specific scenarios such as CNS disease.

Cancer Network: Thank you so much for joining us today, Dr. Loi.

Dr. Loi: You’re welcome, thank you for talking to me.