Advanced Breast Cancer - Episode 6

APHINITY Trial: Adjuvant HER2-Targeted Therapy in HER2+ BC


Debu Tripathy, MD: Joyce, you have been involved in many of the adjuvant trials, and I always like to hear your insight regarding how you parse out benefits. And 1 of the key issues, you know, is what are the contributions of the different drugs we’re using, particularly with pertuzumab, in the actual adjuvant setting? And then, of course, there are new data from San Antonio Breast Cancer Symposium for the lower-risk group of patients.

Joyce A. O’Shaughnessy, MD: Right, right. We’ve got 2 important adjuvant experiences from San Antonio. The first was the 6-year update on APHINITY, which is the adjuvant trial of pertuzumab. This was a physician’s choice of an AC-T [hydrochloride, cyclophosphamide, paclitaxel] backbone or a TC backbone, and patients all got trastuzumab. If you were TC [docetaxel, cyclophosphamide] with the trastuzumab, AC [hydrochloride, cyclophosphamide] would be given first, followed by the taxane with trastuzumab plus or minus pertuzumab. The pertuzumab was given for a year. It was in the adjuvant setting. At the sixth-year follow-up, survival was still very, very immature. Thankfully it’s trending in the right direction—0.85—but it definitely is not significant. Then the hazard ratio for the primary end point, which is invasive disease-free survival, is 0.76. The absolute benefit is 2.8% in the intent-to-treat population at this time.

When you look at the node positive versus node negative, all the benefit is in the node positive. We had seen that before, and that held up. What changed a bit is that they had looked at the ER [estrogen receptor]—positive versus ER-negative. Before it looked like all the benefit was in the ER-negative group, but that’s no longer the case. There were more events in the ER-positive group, which just takes longer to develop. There’s very nice benefit as well in both ER positive and ER negative. There are very reassuring data. I don’t think it changes our practice.

The issue that is a little complex for us is that because we’re giving the treatment preoperatively, and because somebody is clinically node negative as best as you could possibly tell, we do use preoperative pertuzumab if patients have T2 or above disease, you know? But then if they have a pathologic complete response [pCR] and you don’t see any fibrosis in the lymph node, etc, do you continue with the full year of trastuzumab and pertuzumab? Or do you just go with trastuzumab?

Now, I will point out that the FDA label is very clear on this. The FDA label says that if you start with preoperative pertuzumab, you finish the adjuvant experience with pertuzumab. But I think given the APHINITY data and no benefit in the node-negative group, this is certainly open for discussion as the new data develop. But I don’t think it really changes our practice too much. I think it’s just reassuring, except we still have to wrestle a little with somebody who’s clinically node negative. We give them treatment. They get a pCR. What do we do?

Debu Tripathy, MD: For our lower-risk patients, we have new data as well. But maybe to finish this discussion I’d like to hear more on prolonged treatment with pertuzumab. You’re right, Joyce. My feeling is that we don’t have a way to discern, specifically. We’ll probably never do a randomized trial testing the maintenance. But clearly, there is a path forward for de-escalation with the…

Adam M. Brufsky, MD, PhD: I think we’re already kind of parsing the patients in our mind anyway. I mean, those with T2 and above are going to get neoadjuvant therapy anyway. For people who are T1, I think we’re moving more toward surgery first. I think we’ve already kind of done that in our minds, and we’ve already parsed out the patients. The patient you’ve already chosen for neoadjuvant therapy, even if they have a pCR, is likely someone for whom I would continue the pertuzumab in, you know? Whereas someone who’s T1 is probably going to get surgery up front. And then if they are node negative, we’re going to talk about what we would think about doing.

Hope S. Rugo, MD: I think it’s really interesting. Everybody seems to be very much focused on if you get a pCR. Then you should absolutely continue double antibodies for the rest of the year. But I like giving neoadjuvant therapy to patients. To me, I would still give it to a patient who has clinically node-negative disease. I think some of the previous studies that have suggested that there’s a lot of occult node positivity we’re somehow missing.

First of all, APHINITY didn’t look at duration. It wasn’t able to because it was going to be huge and too expensive. It’s unfortunate with the realities of this. But also, now we ultrasound, we examine, we get MRIs [magnetic resonance imaging tests], and we are much better at picking up nodes. Where we miss it is lobular cancer, you know?

We’re not missing it in HER2-positive disease so much, I don’t think. I’m actually more in this camp of saying that if you get a pCR, I don’t there’s much purpose in continuing the pertuzumab for the rest of the year. But if you have a lot of bulky disease, I definitely would. We now have very good data in node-positive disease.

Adam M. Brufsky, MD, PhD: The question then is, now we’re going to introduce subcutaneous formulations of these, if they ever take off in the US [United States]. Will that change your thought process about how you would use it?

Joyce A. O’Shaughnessy, MD: Just 1 other point I want to make is that with the APHINITY trial, this was a year of therapy. Part of that is going to be overlapping with endocrine therapy if you’re ER positive.

Hope S. Rugo, MD: Good point.

Joyce A. O’Shaughnessy, MD: And you know, we know that when you take away the estradiol ligand, here comes neuregulin. It signals down to HER2, HER3. So I don’t mind having trastuzumab and pertuzumab onboard. I guess if we want to get the benefits from the APHINITY trial, we better do the APHINITY treatment.

Transcript Edited for Clarity