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Pegram Discusses Latest Developments in HER2+ Breast Cancer

Shannon Connelly
Published: Wednesday, Aug 09, 2017

Mark Pegram, MD
Mark Pegram, MD
Although tremendous advances have been made in HER2-positive breast cancer, Mark Pegram, MD, says researchers are just getting started.

“Everyone thinks that since we have good therapies for HER2-positive metastatic disease, that our work is done. We are far from finished. Too many patients die from this disease. It’s 20% of breast cancers globally. With metastatic disease, that is a lot of lives,” said Pegram, who spoke on the topic during the 16th Annual International Congress on the Future of Breast Cancer. 

In an interview with OncLive at the meeting, Pegram, associate director for clinical research and director of the breast oncology program at Stanford Women’s Cancer Center, discussed emerging treatments in HER2-positive breast cancer and his vision for the future of the field.

OncLive:  Please provide an overview of your presentation.

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 (ado-trastuzumab emtansine; Kadcyla) in the second-line, based on the EMILIA pivotal trial, which was published in the New England Journal of Medicine just a few years ago. There was also a recent publication with the updated overall survival 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 the Journal of Clinical Oncology, suggesting that there is significant clinical benefit in T-DM1–treated patients, even after prior pertuzumab. That sets the stage for the standard of care currently in 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, particularly in 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. 

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