Breast Cancer: Dual HER2-Targeted Adjuvant Therapy



Adam M. Brufsky, MD, PhD: Let’s talk about the other big trial that was announced, APHINITY, at ASCO and was published in the New England Journal of Medicine over the summer. So, Michael, what do you think of APHINITY? Can you describe APHINITY for our viewers?

Michael Untch, MD: Yes. So, after the successful story of trastuzumab in the adjuvant setting, obviously we were asking ourselves what can be done to make this treatment even better in HER2-positive disease. And actually, APHINITY was designed to ask the question whether chemotherapy with trastuzumab compared to chemotherapy with trastuzumab and pertuzumab—so double blockade with two antibodies—is going to give us a difference.

Now to come back maybe to the story of neoadjuvant treatment, and you mentioned that from a small trial with 112 patients, there was an approval at the FDA. The same happened with the double blockade with trastuzumab and pertuzumab from NeoSphere because this led to FDA approval from a 112-patient portion from the study group. It was a provisional approval and obviously, we were very curious to see what happens in APHINITY.

So, in APHINITY, 5000 patients were prospectively randomized and now presented at ASCO as an oral presentation this year. Primary endpoint was met with a significant difference in invasive-free survival, which was exactly 1% in the total population and 2% in the node-positive population. Now this is not something that takes us off the chair because we had such a positive influence of the trastuzumab adjuvant trials in the past 10 years, then probably we were waiting for a huge or a much better Kaplan-Meier code. But the bottom line is, how can you improve a 95% or 96% invasive disease-free survival? So, 1% was a positive difference, and in the node-positive cohort, it was even better. On the other hand, node-negative patients at this time point was not a significant difference.

The question is, what are we going to make out of these data? Are we going to treat all patients with double blockade who are HER2-positive patients, or just node-positive disease? At the moment, at least in Germany, most patients with HER2-positive disease are treated in the neoadjuvant setting with a double blockade. So, we’re not going to ask the question about node-positive or node-negativity, we just treat a patient with a double blockade. It might be different in other countries. It might be different in United States.

Adam M. Brufsky, MD, PhD: Most of us in the United States will treat patients with a T2 or beyond with neoadjuvant therapy.

Joyce A. O’Shaughnessy, MD: Or node-positive.

Adam M. Brufsky, MD, PhD: So, the question becomes, where do these agents fit in? I think that we’ve got to put this together for people who are watching this, and in our own minds as well. Everybody, at least in the United States, who’s going to get neoadjuvant therapy will get dual blockade. So, they’ll get TCHP or ACTHP or something like that.

Hope S. Rugo, MD: Go back a little bit. It does bring up the question, if you have a patient who has ER-positive HER2-positive disease who has node-negative tumor that’s 2 cm, and you’re going to give them neoadjuvant therapy, do they need pertuzumab? I just had a patient refuse pertuzumab.

Adam M. Brufsky, MD, PhD: Hope, I totally agree with you. So, that brings a whole other issue to play. You now have these women, it used to be that our surgeons in the United States would send us people with T1 disease that’s HER2-positive because it was the only way to get pertuzumab in the United States, the only way to get it approved. Now, it’s approved postoperatively. The first question to you, Hope, is do you think there will be a group of patients who normally you would have given neoadjuvant therapy to who no longer will get it because of that? Because now if they turn out to have high-risk disease after surgery, they’ll get pertuzumab in the adjuvant setting?

Hope S. Rugo, MD: So, you’re suggesting that the 1% difference will lead to FDA approval of an antibody that’s very expensive and that’s given every 3 weeks for a year?

Adam M. Brufsky, MD, PhD: I’m asking, I don’t know. Let’s bring it up.

Hope S. Rugo, MD: I think that we may need a little bit longer duration data. There’s a little bit bigger separation of 4 years, but there are not a lot of data maturity, and the node-positive patients were added in late. There’s a lot of different issues, which means that we probably do need to wait a little bit to see more data. But I think that we never saw curves substantially change in HER2-positive disease so far. So, I’m not holding out a big hope that we’re going to see something completely different.

But I think actually that we’ll still use neoadjuvant therapy. It’s a way to understand how patients are doing, and that’s going to be critical for us to understand who’s more likely to benefit, for example, from an alternative therapy like adding in neratinib at the end of a year. So, if you have patients who don’t have a path CR with ER, particularly those with ER-positive disease, these are patients who I would be much more interested in giving neratinib to than somebody whose disease completely melts away in the first 2 weeks of neoadjuvant therapy, where we don’t think we’re doing a whole lot with giving more therapy.

Adam M. Brufsky, MD, PhD: So, what I’m hearing then is that someone whose disease melts away will not get any of these agents, pretty much.

Hope S. Rugo, MD: Well, no. We finish a year of trastuzumab. I don’t even know that they need a year of pertuzumab. They didn’t study a shorter duration, so it’s hard. I wish that we’d had the ability within that; it looks like the trial was hard enough without that question. But it’s really important. If you have a path CR at the end of your neoadjuvant therapy, we don’t really know that you need the pertuzumab to continue for a year. Maybe you’re good enough and you could just do trastuzumab and your hormone therapy as indicated. It’s really hard to know.

Adam M. Brufsky, MD, PhD: Michael, you had a comment?

Michael Gnant, MD: I guess that’s that the issue we’re struggling with in applying the APHINITY data to clinical practice because in many of the, let’s say, advanced environments, clinical practice has overtaken the provision when the trial started. We would do very proactive or would say aggressive dual blockade for all HER2 patients down to T1C because it’s not about tumor size, it’s about the pCR. Because we know that in this subset pCR is excellent for long-term outcomes. We fight for pCR. And after all, this is 50% to 70% of patients with dual blockade in these tumors.

What we are currently doing, fortunately we can use pertuzumab in the adjuvant setting, but we do this in node-positive disease or maybe node-positive receptor-negative HER2-positive disease. So, the more receptor-negative, the more node-positive you are, the more likely you are to get off an additional 6 months of the dual blockade, which virtually everybody has in my environment in the neoadjuvant setting.

However, having said this, I think the majority of our colleagues—at least globally definitely, but even in the rest of the world—may not have such an aggressive use of dual blockade in the neoadjuvant setting. So, for them, it’s a completely different story. And definitely in resource-limited environments, it’s a completely different story. And I think we urgently need them based on the excellent overall outcome. And remember, 15 years ago, what was the overall outcome of HER2-positive disease? It was lack of efficacy.

Adam M. Brufsky, MD, PhD: We all remember what HER2 disease was, we all remember that.

Michael Gnant, MD: Exactly. So, what we urgently need is de-escalation trials. Identify who cannot have adjuvant treatment, can have shorter duration or maybe single-agent completion.

Hope S. Rugo, MD: Yes. But see the way for this is neoadjuvant therapy. So, you give neoadjuvant therapy, you evaluate part way through, and everybody’s working on this now. And then the people who are going to get a pCR, you could actually do a little less therapy. And the people who aren’t responding, you do more therapy, you add something else in.

Transcript Edited for Clarity

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