HER2+ Breast Cancer Paradigm Evolving With Practice-Changing New Options

Mark D. Pegram, MD

Breast cancer treatment has evolved dramatically over the past 2 decades, said Mark D. Pegram, MD, and several approaches are emerging for those with HER2-positive metastatic disease in the form of new antibody-drug conjugates (ADCs) and small molecule inhibitors.

“Back when I started my training, around that same timeframe of over 20 years ago, we treated patients pretty much the same based on their stage and their steroid receptor status; that was about it,” said Pegram. “Then came HER2 and the first biologic agent ever approved by the FDA for the treatment of breast cancer: trastuzumab (Herceptin). Now, we are looking at multiple biologic agents on the cusp of approval.”

Some of these agents coming through the pipeline, such as margetuximab, tucatinib, and [fam-] trastuzumab deruxtecan (DS-8201), have investigators optimistic about what the future will bring. Moreover, the rise of biosimilars in the United States may provide patients with more accessibility to potentially life-saving drugs, predicted Pegram.

“We are in the early days of precision medicine,” said Pegram, co-director of Stanford University’s Molecular Therapeutics Program and director of the Breast Oncology Program at Stanford Women’s Cancer Center. “I expect the next generation [of researchers] will build on this. That’s the way it should be.”

OncLive: What have been the most exciting data in the HER2-positive breast cancer space?

In an interview with OncLive, Pegram highlighted data from pivotal studies that have helped to shape the current landscape of HER2-positive breast cancer and shed light on emerging agents that are showing promise in the pipeline.Pegram: There has never been a more exciting time to be in the area of clinical research and clinical investigation for HER2-positive breast cancer. Some might say that there is not much work left to be done, particularly in early stages of HER2-positive breast cancer, because of the results of the adjuvant trastuzumab plus chemotherapy trials. These studies, from over a decade ago, were so spectacular that some people feel the “heavy lifting” is over.

If you look at the 3-year outcomes from all the trastuzumab trials back in the day, all of them at year 3 look spectacular with 80% to 90% invasive disease-free survival rates. Now, we have new 10-year data, which a lot of practitioners are not aware of. All of these trials have an estimated 25% relapse rate at year 10. Sadly, there is still work left to be done in early-stage disease. Moreover, [work remains] in the metastatic setting as well, because of the 25% relapse rate by year 10. Consequentially, the majority of those relapses are distant metastatic relapses instead of locoregional relapses.

However, the good news is that there are several promising and exciting agents that are coming through clinical trials, some of which are going to be approved soon. These include extended adjuvant HER2-targeted therapy with small molecule inhibitors, such as neratinib (Nerlynx) and the addition of a second HER2-directed antibody to trastuzumab, such as pertuzumab (Perjeta), which did show—although a modest benefit—a statistically significant and possibly clinically meaningful benefit in a select group of patients.

Now, we also have data from the KATHERINE trial on adjuvant ado-trastuzumab emtansine (T-DM1; Kadcyla) in patients who failed to achieve a pathologic complete response (pCR). Those data are wildly positive; if you look at the hazard ratio, it is 0.5. That's the same as what was seen in the adjuvant trastuzumab trial. If you look at the point estimates of the hazard ratios from both of those trials, they are almost the same. The adjuvant trastuzumab trial in 2005 got a standing ovation at that year's ASCO Annual Meeting and Gabriel N. Hortobagyi, MD, of The University of Texas MD Anderson Cancer Center wrote an editorial published in the New England Journal of Medicine, stating that these data were "simply stunning" at the time.

How will the results of the KATHERINE study shift focus in the adjuvant setting?

The adjuvant T-DM1 data are essentially the same numbers, albeit in a different patient population. Nevertheless, those numbers are impressive and, indeed, practice-changing. Therefore, these are some of the things that are exciting, but there is more work left to be done and a lot of ongoing work is exploring promising therapies for the metastatic setting, which will translate to early-stage disease at a later date.First, the stunning results from the KATHERINE trial will change practice. Secondly, those data will also change the way that we use HER2-targeted agents. To date, we had the option of adding a second HER2-directed antibody for high-risk patients. However, now we have an actual biological read using pCR in the adjuvant setting.

Could you expand on the promising investigational agents in the metastatic setting?

As such, I believe that many clinicians may be more enthusiastic now to look at neoadjuvant therapies, that way they can tailor the treatment based on pCR or lack thereof. T-DM1 offers a whole new option; it will replace pertuzumab for 1 year in those patients who fail to achieve a pCR. Now, those patients will all be switched to T-DM1, thanks to data from the KATHERINE trial, so that’s a major change in treatment. These are provocative data that will change the way that we think about treating patients with early-stage disease in the future. [These data will] probably even shift our considerations for the use of a neoadjuvant approach when clinically feasible, or even necessary for other endpoints, such as breast conservation therapy, resectability, etc.The HER2-positive metastatic disease space is even more intriguing in 2019. There are several new and novel approaches that appear to be effective. We are in the early stages with these agents—mostly phase II, but some phase III trials—at this point. One target to exploit is antibody-dependent cell killing by natural killer (NK) cells. This can be accomplished by engineering the Fc domain of a HER2 antibody, so that it binds more tightly to activating Fc gamma receptors on white blood cells, namely NK cells. That stimulates those NK cells to release granzymes and perforins that attack the tumor target with HER2 targeting on the other end of the molecule, same as trastuzumab. That can elicit cell-killing mechanisms, and the engineering increases the affinity of the HER2 antibody to the Fc gamma receptor-activating molecules on the surface of the NK cell compared with trastuzumab.

There is a phase III trial that has recently been the subject of a press release; we have yet to see the data. Hopefully, we will see those data at the 2019 ASCO Annual meeting; the phase III data based on the press release are expected to be positive. An engineered HER2 antibody outperforms trastuzumab—that's a change. The concept of perhaps replacing trastuzumab some day is not something that investigators have even considered. Clinicians will understand that, and maybe this will be the case with these Fc antibodies.

Another approach that is exciting is the use of new ADCs. We already mentioned the efficacy of T-DM1 in the adjuvant setting. Of course, this agent has activity in the metastatic setting as well, which won the original FDA approval of the drug following trastuzumab and a taxane.

Now, there are second-generation HER2 ADCs that are in clinical development and they look very promising. One is DS-8201 and it has very impressive activity against HER2-positive tumors, not just in breast cancer but across multiple tumor types. There is also [vic-]trastuzumab duocarmazine (SYD985) , which has shown impressive activity against HER2-positive breast cancers. At the 2018 ASCO Annual Meeting, both of those molecules showed activity in HER2-low cases; these are cases that would otherwise be considered HER2 negative. They lack gene amplification and do not have 3+ overexpression; instead, they have 1+ or 2+ expression. Yet, these drugs have impressive efficacy even in those patients. That may open up an entirely new [option for] patients who we would never consider for HER2-targeted therapies. Now, we have something for them. That is totally unexpected.

How does the recent FDA approval of subcutaneous trastuzumab impact clinical practice?

Finally, there are new small molecule HER2 inhibitors that are in late-phase development. One of these drugs specifically targets HER2. The problem with lapatinib (Tykerb) and neratinib is that they are not pure HER2 inhibitors; they inhibit other HER family receptors, such as EGFR. That is an off-target type of event that just leads to excessive toxicity in the form of diarrhea, cutaneous rash, etc. A pure HER2 inhibitor, in theory, would have less toxicity. Moreover, tucatinib, one of these pure HER2 inhibitors, also gets into the brain and has good activity against brain metastases.Ironically, the Europeans have had access to subcutaneous trastuzumab for many years already. It was a simple trick to get antibodies to be absorbed well from the subcutaneous space using another formula called recombinant hyaluronidase. That's required to digest the proteins into the extracellular space to allow diffusion of the large macromolecular antibody therapeutics into the circulation. That’s required, but it has been available for probably a decade. However, it is just now coming into the United States commercial market for the first time. Its [benefit has been] proven and it's tried and true in head-to-head comparisons with intravenous trastuzumab. Those data look super imposable.

With the plethora of biosimilars coming through the pipeline, how do you see these agents impacting the field?

Subcutaneous trastuzumab may well have some impact on the use of a trastuzumab biosimilars because of its ease of use. Some people may be willing to pay a premium for its ease of use. It's going to make things interesting in the space. Now, if margetuximab is a big success, it might replace all of these possibilities.Biosimilars have been around for a very long time, particularly outside of the oncology space. The biosimilar antibodies used to treat inflammatory bowel disease have been available globally for many years. Biosimilar hemopoietic growth factors have been available for many years. The HER2 biosimilars will parallel those other fields. There could be winners or losers. There are approximately a half dozen trastuzumab biosimilars in development as we speak—some of them will be competitive and gain traction while others will face the constraint that antibodies are expensive to manufacturer. Even biosimilars [can be expensive]. There is a lower bound on cost that all of those biosimilars are up against because you can't sell something for cheaper than you can manufacture it. The prices may gravitate toward that boundary. They won't all make [the cut].

It might be even more difficult for us as clinicians to choose which agent to use because they are similar—highly similar. That is, indeed, the requirement for FDA approval. It is going to be very difficult [to choose], and a lot of it may come down to cost; it will be on a cost basis that many hospitals choose which ones to use at their institutions. Patients outside the United States who can't afford the brand name product may now be able to afford trastuzumab biosimilars. That's a plus; it's a good thing. That's why the patent laws are structured the way they are.