Pertuzumab Plus Trastuzumab for Early-Stage HER2-Positive Breast Cancer

8-Year Data From the APHINITY Trial

In this expert roundtable series, Reshma Mahtani, DO, Miami Cancer Institute, Florida, leads a 4-part panel discussion on the management of patients with HER2-positive breast cancer with Terry Mamounas, MD, Orlando Health Cancer Institute, Florida, and Jane Meisel, MD, Winship Cancer Institute, Atlanta, Georgia.

In the last part of this discussion, our experts highlight 8-year updated results from the APHINITY trial and reflect on the progress that has been made in the setting of HER2-positive breast cancer.

Transcript:

Dr Reshma Mahtani: Here we'll focus a bit on the APHINITY trial and the 8-year update. Jane, do you want to start by giving us a background on this study and the schema and who was enrolled, and then, Terry, I'll ask you to comment on the updated data?

Dr Jane Meisel: Sure. The APHINITY study was conducted between 2011 and 2013, so it enrolled patients quite some time ago now. It was almost 5000 patients with HER2-positive, early-stage breast cancer. Patients were assigned to receive adjuvant treatment with either dual or single HER2-blockade plus chemotherapy, so all these patients were treated in the adjuvant setting. Patients received either trastuzumab or trastuzumab plus pertuzumab as their adjuvant anti-HER2 therapy.

There were about 34% node-negative patients, patients who were hormone-positive were about 64% and 78% of these patients received anthracycline. It was a slightly different population than the population we're seeing today, because most of our patients with the more locally advanced disease are being treated neoadjuvantly, and as we said, a lot of institutions are moving away from anthracyclines. This is still a really helpful study in thinking about which anti-HER2 therapies are we giving, particularly after the chemotherapy is done.

This is the third interim analysis. The data that most recently came out after about 8.5 years of follow up. And I can pass that on to Terry to describe what the data showed.

Dr Terry Mamounas: What the study showed essentially is that there was a sustained benefit with T-DM1 at 8 years in the range of about 3% or so for the overall trial, and moreso for patients with positive nodes, which was about a difference of above 5%. For node-negative patients, there's still not a lot of benefit, because those patients obviously are low-risk and there was no survival benefit.

But this clearly solidified that the addition of the antibody does improve outcome for patients that have positive nodes, and even more so for patients with 4 or more positive nodes—this was the group that benefited the most. It solidified the approach of including pertuzumab in the neoadjuvant setting, which was, as you know, an accelerated approval by the FDA at the time. The FDA wanted more EFS data, both in the neoadjuvant setting as well as in the adjuvant setting, and APHINITY provided that assurance, not for everybody, but mostly for the high-risk patients.

One question I have in my mind is for patients that have a lot of positive nodes in APHINITY, that would've been a great group of patients that potentially you can do T-DM1 at some point because they'd have a substantial risk. And some trials have selected for patients that have a pCR rate after neoadjuvant chemotherapy but high clinical risk, going on stages 3A or 3B, those patients, they have never been included in any of the trials that we do.

But there are some trials now that include those patients as high-risk patients, looking at vaccines and other treatments. We forget about these patients because a lot of people have always said “pCR is a pCR,” but it's not exactly a pCR. You do much better if you’re node-negative and get a pCR versus if you're node-positive and get a pCR, or if you have locally advanced breast cancer and get a pCR. We have to keep that in mind as well in our trials. But yes, the APHINITY clearly showed that for the high-risk patients, pertuzumab does improve.

Dr Reshma Mahtani: Clinical risk definitely is important. If you have more disease to start with, regardless of the pCR, you have a higher risk.

One practical point that comes up quite a bit is for these patients, for example, who were clinically T2N0, who met criteria for neoadjuvant pertuzumab and achieved a pCR, given the data that we have seen in APHINITY, with the benefit in the higher-risk node-positive patients, Jane, how are you handling that situation? Do you have the approach that, if it's not broke, don't fix it? That's what got them to the pCR, so just continue the adjuvant pertuzumab. Or do you feel that in these node-negative patients, there's really not a benefit and you're just doing trastuzumab in the adjuvant setting? How are you approaching it?

Dr Jane Meisel: We talked about how sometimes when they're clinically node-negative they can still be node-positive at the end of the day. For these patients, where sometimes at the time of surgery our pathologists will be able to look at the nodes and even if they're negative at the time of surgery, they'll see the treatment effect. Those are the patients where I worry a little bit about whether they were in fact clinically node-positive and we just didn't catch it. And especially if they're young and tolerated treatment well and I have more concerns about recurrence, I might continue the pertuzumab along with the trastuzumab, if insurance will allow it.

But there are patients who didn't have as easy of a time with treatment and for whom I do feel fairly certain that there was no nodal involvement. Since the benefit of APHINITY really was limited to those node-positive patients, then I just continue the trastuzumab afterwards. It is one of those individualized decisions and because it's a challenging space in terms of the data, I try to make as much of the decision with my patients as I can, but not leave it totally up to them. Because it is challenging for patients and they do want to be guided by our decisions.

Dr Reshma Mahtani: I agree. Terry, anything to add about that clinical situation and how you approached it?

Dr Terry Mamounas: The only thing I can add is that sometimes you're not 100% sure that these patients were always node-negative, right? They could have been sub-clinically node-positive before, and sometimes you may see treatment effect in the nodes and you said that they were positive before and became negative. Those patients I would like to continue. But if there's absolutely no treatment effect, you can argue that maybe they were node-negative all along, but it is that bit of information as well that we don't know at the start.

Dr Reshma Mahtani: And it's notable also that in trials, like the Compass studies that we were referencing earlier, they're continuing HP in the adjuvant setting in those studies as well. That’s important to note.

Do either of you have any closing comments on this discussion? Not focusing on APHINITY, but any closing comments?

Dr Jane Meisel: This has been a great discussion and it's amazing when I think back on the timeline of development of HER2-directed therapies and how many more options we have now than we had even a couple of years ago. All the really exciting clinically relevant trials that are enrolling quickly and where we will have information coming soon. This landscape will continue to change and hopefully continue to become even more personalized so we can continue giving the right treatment to the right patients and giving them the best outcomes possible.

Dr Reshma Mahtani: Absolutely. Great news for our patients to progress. Terry?

Dr Terry Mamounas: I would echo this comment. I remember in my career having patients who didn't do as well with the treatment, with endocrine therapy, with chemotherapy, and you always wondered what it was. And then in retrospect, when trastuzumab became available, we tested these spaces that were HER2-positive. It's amazing the progress made in this subtype of disease, making it from one of the most aggressive subtypes to one of the best subtypes to treat at this point.

In fact, they're as good as ER-positive, HER2-negative for small tumors, but for bigger tumors, they're way better. We always hope that we have HER2-positive disease when we see locally advanced, because if it’s ER-positive, HER2-negative, it's, much more of a tougher proposition for the patient.

Dr Reshma Mahtani: Isn't it so surprising now, younger physicians actually think of HER2-positive disease as the better type of breast cancer, because of the progress we've made. And for those of us who have been doing this quite a while, we understand the fact that HER2-positive disease by itself is very aggressive, and seeing how that view of the treatment has changed and evolved has been a testament to the progress that we've made. It's great news for our patients. I'd like to thank you both for joining me today.

This has been a wonderful discussion and hopefully everyone got a lot out of it. And thanks again.