Pegram Highlights a New Renaissance of Research in HER2-Positive Metastatic Breast Cancer

Mark Pegram, MD

The field of HER2-positive metastatic breast cancer is currently in the midst of a renaissance, says Mark Pegram, MD, with a tremendous resurgence of developments in the disease and a wide range of research now ongoing.

“There are a lot of developments,” Pegram said. “This is truly a new renaissance of research in HER2-targeted therapy in the metastatic setting and hopefully, if we win success in metastatic disease, this can be translated into earlier-stage settings in the future.”

Pegram, associate director for clinical research and director of the breast oncology program at Stanford Women’s Cancer Center, recently gave a presentation on new insights into HER2-driven metastatic breast cancer management during the16^thAnnual International Congress on the Future of Breast Cancer.In an interview withTargeted Oncologyduring the congress, Pegram shared some of the most recent developments in the HER2-positive metastatic breast cancer space, the research currently ongoing, and why it is such an exciting time for the field.

TARGETED ONCOLOGY:Can you give an overview of your presentation on new insights into HER2-driven metastatic breast cancer management?

Pegram:Right now, based on level 1 evidence, we have good data to support the use of pertuzumab (Perjeta) in combination with trastuzumab (Herceptin) and chemotherapy in the first-line setting. That's usually followed by T-DM1 (trastuzumab emtansine) in the second-line, based on the EMILIA pivotal trial, which was published in theNew England Journalof Medicinejust a few years ago. There was also a recent publication with the updated overall survival (OS) analysis, which remains significant.

Although EMILIA was not done in the pertuzumab metastatic breast cancer era, we still, by extrapolation, assume that T-DM1 will retain activity. Now there is some literature from retrospective reviews. There was a series recently published in theJournal of Clinical Oncology, suggesting that there is significant clinical benefit in T-DM1-treated patients, even after prior pertuzumab. That sets the stage for standard of care currently in standard practice and guidelines. In the third-line, lapatinib (Tykerb)-based regimens are frequently used.

That begs the question what would be next in terms of excitement for HER2-positive disease, or is this current paradigm the end-all and the best we're going to do for this disease. The answer is that we're enjoying a renaissance, a tremendous resurgence and interest in HER2-positive disease with many exciting trials and new molecules that are being introduced. For example, there are FC-engineered antibodies, like margetuximab, that have an enhanced immune effector function, meaning greater immunologic responses with an anti-HER2 antibody. That is now in a phase III pivotal trial that is ongoing. It will be interesting if it can beat trastuzumab plus chemotherapy, which is the control arm in a salvage setting in that trial.

There are new, HER2-specific small molecule orally bioavailable tyrosine kinase inhibitors (TKIs). In the past, drugs like neratinib (Nerlynx) and lapatinib, while they hit HER2, they also hit the epidermal growth factor receptor (EFGR), which causes many EGFR toxicities, such as cutaneous toxicity, and GI toxicity that can be particularly problematic. Consequently, the new drug, tucatinib (ONT-380), has less GI and cutaneous toxicity compared to the other HER2 TKIs, which is a consequence of its specificity for HER2 and less overlap with EGFR. That is now in a pivotal phase III trial — an FDA registration trial – that's going to be exciting if it gets approved. It also has CNS penetration, which is great news.

There are also new antibody drug conjugates. It turns out, T-DM1 probably won't be the last HER2 antibody drug conjugate. It has some limitations, at least in theory, in particular, internalization rates. It turns out that the rate of internalization of the antibody drug conjugate is very important for its activity in killing tumor targets. It seems that HER2 is a relatively internalization-resistant receptor. One way to improve the internalization rate is to use a bispecific HER2 antibody that binds to both the pertuzumab epitope and the trastuzumab epitope in subdomains 2 and 4 of the HER2 extracellular domain. Instead of binding to both those epitopes on the same molecule with a bispecific antibody, it actually crosslinks adjacent molecules, setting up a lattice in the membrane, which is a potent stimulus for rapid internalization by receptor-mediated endocytosis. These new antibody drug conjugates are in the clinic already. There's one from MedImmune that's in phase I at our center and others. There is soon to be one from Zymeworks that has a similar bispecific construct targeting both subdomains 2 and 4 of the HER2 receptor. These are exciting developments and perhaps we'll have new opportunities with antibody drug conjugates. There are other ways of augmenting immunity with trastuzumab or with T-DM1. For example, there is some data showing synergism with checkpoint inhibiting antibodies. That's an exciting area of new research with ongoing trials with T-DM1.

There are also ways to activate antibody-dependent cellular cytotoxicity using agonist antibodies against CD137. At our center, we have an investigator-initiated trial looking at that combination. There are a lot of developments. This is truly a new renaissance of research in HER2-targeted therapy in the metastatic setting and hopefully, if we win success in metastatic disease, this can be translated into earlier-stage settings in the future.

TARGETED ONCOLOGY:What do you envision for the future treatment landscape of HER2-positive breast cancer?

Pegram:It's likely that we could conceive of combining some of those strategies together. For example, there's no reason why you couldn't give a HER2-specific TKI, like tucatinib, along with a HER2 antibody or an FC engineered HER2 antibody. You could envision giving margetuximab, the FC engineered antibody, along with a CD137 agonist antibody. Perhaps they would synergistically enhance antibody-dependent cell-mediated cytotoxicity activity even more. As I mentioned, the checkpoint antibody combinations are obvious and will be explored thoroughly in the clinic. I suspect that we'll see more and more combinations of HER2-targeted therapies, rather than just single-agent use for these new therapeutics.

TARGETED ONCOLOGY:What are the most pressing challenges still facing this field?

Pegram:There are big challenges, mainly regarding safety signals. With HER2 TKIs, while they are active, they are difficult to give in some situations because of diarrhea. Even with new drugs like tucatinib, even though they have less diarrhea, it's still not zero. We'll still have to be mindful of off-target toxicities, even with the newer agents. The antibody drug conjugates, while a breakthrough in terms of tolerability and efficacy, they still have some chemo-like side effects. We have to worry about liver function test abnormalities, in the case of T-DM1, we have to worry about thrombocytopenia and neuropathies. I think safety is going to be the biggest hurdle to overcome with any of the new emerging technologies. Certainly, with immunotherapies, we need to worry about off-target autoimmune phenomenon, for example, which is all very concerning. The phase I and phase 1b trials will have to be done very carefully to find the safe and efficacious doses.

TARGETED ONCOLOGY:Where are we currently with biomarker research in HER2-positive breast cancer?

Pegram:Biomarkers have been a tough battle in HER2-positive disease and in breast cancer in general, but not for lack of trying. There have been tens of thousands of publications on breast cancer biomarkers, and yet in the clinic we use a select few. I think that will change. I think circulating tumor DNA will be useful to monitor metastatic disease. For example, you might be able to either decrease or perhaps eliminate the need for restaging imaging studies if you have a quantitation of circulating tumor DNA, which is reflective of total body tumor burden. Hopefully, that will be the case. That's well positioned and can be tested. In earlier stage disease, I think the circulating tumor DNA isn't quite sensitive enough for small node negative tumors. Maybe for locally advanced, there would be a signal there, but we'll have to see. I expect the technology will continue to improve. Perhaps another order of magnitude or so in sensitivity would win interest for neoadjuvant or adjuvant therapy situations.

There is a huge list of interesting targets based on TCGA and METABRIC expression array data that's been around for years. We're certainly using the expression array subsets of triple negative disease to inform future clinical trials in that type of breast cancer, and I think the same could be applied in the future of HER2-positive disease.

TARGETED ONCOLOGY:What is the takeaway message from your presentation?

Pegram: