Advancements in Treatment and Management of HER2-Positive Early Breast Cancer: Introduction and the APHINITY Trial

Jacob Kettle, PharmD, BCOP, and Allison Butts, PharmD, BCOP, share insights on some recent trials for early stage breast cancer, specifically the APHINITY trial.

Jacob Kettle, PharmD, BCOP: Hello, and welcome to this Pharmacy Times® Insights discussion on “Advancements in the Treatment and Management of HER2-Positive Early Breast Cancer.” My name is Jacob Kettle. I’m a pharmacist at the University of Missouri Health Care, and I’m joined today virtually by my colleague from the University of Kentucky [College of Pharmacy] Allison Butts. We are going to be discussing today a number of topics pertaining to updates in therapy for early stage breast cancer and changes we’ve implemented in our practices in response to the coronavirus pandemic. Without further ado, let’s get started with our first topic.

It’s critical when we talk about HER2 [human epidermal growth factor receptor 2]—targeted breast cancer that we remember that it’s been 2 decades since trastuzumab radically shifted the landscape. We have to keep in perspective, in the absence of targeted molecules, that HER2 is a negative prognostic indicator. We know that still roughly 1 of 4 women will relapse within 10 years, even treated with trastuzumab. This is pivotal because, typically, when you have that relapse, you’ve lost the cure potential. Likewise, continued innovation remains essential. That’s precisely why today’s discussion is so important and exciting.

Let’s go ahead and dive in and talk about some of the new molecules available for HER2 patients. This is where we’ll bring you in, Allison. I’m glad to be able to rely on your clinical expertise here. We now have a handful of additional HER2-targeted molecules that we can use to augment trastuzumab therapy, particularly in the early stage breast cancer space. My first question, and we’ll go through these 1 by 1, is this: Where do these fit in, or how do you reconcile risk versus benefit?

The first drug I want to talk about is 1 that’s probably been on the market the longest, and that’s pertuzumab. We recently got an update from the APHINITY trial; it’s a 6-year update. It showed continued improvement: a decrease in invasive disease-free survival at 6 years. The gap seems to widen a bit over time. That difference absolute was 90.6% versus 87.8% when pertuzumab was added to chemotherapy versus trastuzumab. I’m curious: What are your thoughts on that data and some of the ins and outs of that study?

Allison Butts, PharmD, BCOP: As you pointed out here, the APHINITY trial is an important trial for a number of reasons. We’ve been using pertuzumab in other spaces for quite some time, but it’s the first time that we’re looking at it more in the adjuvant space. There are a couple of things to point out about the study itself before we get into the results. As a reminder to everybody watching, we’re talking about a study that looked at a year of pertuzumab therapy adjuvantly, so there was no neoadjuvant therapy—purely 1 year of therapy adjuvantly with their trastuzumab therapy.

The authors presented their 3-year results, and they found an improvement in invasive disease-free survival but only about 1%. No less, this was enough for the FDA to expand its indication to include the adjuvant patients who weren’t previously included in the indication. More recently, in December, the authors presented their longer-term follow-up of about 6 years’ time. Again, the invasive disease-free survival benefit is modest. However, it was increased to more like 3% at that point, so we did see those curves separate a little more with time. There was no overall survival difference though, so that’s important to keep in mind too when we’re justifying potentially adding this therapy: We need to think about what outcomes we are affecting in exchange for adding another therapy, its cost, its toxicities, etc.

The other key point that is necessary with this particular trial and looking at the outcomes is that the benefit was mainly reserved in those patients who are node positive. If you’re looking at a patient and you’re considering adding this therapy, if the patient doesn’t have positive lymph nodes, you’d be hard pressed to consider adding it.

We need to select our patients more closely than that. With this trial, the last comments I’ll make are related more toward some unanswered questions that are generated from the APHINITY data. How do we reconcile this with current practice standards? For most of us, the recommendation now is to treat patients with stage II to III HER2-positive disease neoadjuvantly, likely giving a pertuzumab-inclusive regimen in the neoadjuvant space. If there’s residual disease, the current practice tells us to switch gears and administer ado-trastuzumab emtansine adjuvantly to complete the patient’s year of therapy. It’s hard to say how to use this information, because we shouldn’t be treating these patients adjuvantly only. They should be getting neoadjuvant therapy, and we should then be tailoring their adjuvant therapy based on their response to begin with.

The other complicated, unanswered question then is this: What do you do with these patients who have surprise pathology at the end? This may be a patient who’s clinically stage I. We don’t think they have positive lymph nodes. It seems like a small mass, so we take them to the OR [operating room] first with plans to treat adjuvantly, and perhaps at that time we find out that they’ve got more extensive disease. At that point, do we treat them with a year of pertuzumab? Is that necessary, or is 6 cycles—as they would have gotten neoadjuvantly—just as good?

We need to do more research in this area. We’ve encountered that second scenario, where you end up with a patient with more extensive disease, a few times lately, and we don’t know how many cycles is truly necessary.

Jacob Kettle, PharmD, BCOP: That’s fascinating, and I’m glad you brought that up because you see that elsewhere in oncology too—you have new studies, but by the time they’re published, they don’t have a niche to fit into anymore because of how therapeutics have shifted elsewhere.