APHINITY and ExteNET Trials for Early-Stage Breast Cancer



Adam Brufsky, MD, PhD: Let’s talk about APHINITY. Rashmi, what do you think of APHINITY and the stuff that Martine Piccart presented at San Antonio Breast Cancer Symposium 6 months ago?

Rashmi K. Murthy, MD, MBE: That was a really nice update on the previously presented study, and my biggest takeaway is that the benefit of pertuzumab was seen more in the node-positive patients. Currently, I’m strongly advocating for my node-positive patients to continue pertuzumab for a duration of 1 year. In the node-negative patients, it opens up a real question as to whether we should advocate for them to get HP [trastuzumab, pertuzumab] maintenance or just H [trastuzumab] alone. That becomes a point of discussion with the patient. But I strongly encourage my node-positive patients to continue it for a whole year.

The other interesting piece that came up in APHINITY is that in the updated analysis, there’s really no difference seen between the hormone receptor–positive and hormone receptor–negative.

Mark D. Pegram, MD: If you look at the forest plot in the New England Journal of Medicine, there is absolutely no difference for benefit of pertuzumab in APHINITY based on steroid receptor status. The confidence limits are completely overlapping. The point estimates are very similar, so that was incorrect.

Adam Brufsky, MD, PhD: Some random stuff that has been presented every so often shows that somehow, if you’re a specific luminal subtype, you get more benefit from pertuzumab. That was like wandering around in neoadjuvant circles for a while.

Mark D. Pegram, MD: It hasn’t been shown in the APHINITY data.

Adam Brufsky, MD, PhD: It wasn’t. I agree, but I was thinking that some of that came from—I don’t even remember. Sorry about that, Rashmi. We interrupted. Back to APHINITY.

Rashmi K. Murthy, MD, MBE: Yes, so my 2 key takeaways were really adjuvant pertuzumab for node positive and not differentiating between use of it versus not based on hormone receptor status.

Adam Brufsky, MD, PhD: Let’s go a little further with this. We’re in the era, now, where neratinib has been approved for postneoadjuvant therapy. Are we using it? Are we using neratinib in people? If so, who? Carey, let’s start with you because you are the brain person. You probably use more neratinib than most of us.

Carey K. Anders, MD: Sure. One of the things about the APHINITY data, just to take a step back to where we even get to the end of a year of HER2 [human epidermal growth factor receptor 2]–directed therapy, is the majority of us are giving TCHP [docetaxel, trastuzumab, pertuzumab, carboplatin] neoadjuvantly. Unless something happens where medical oncology isn’t consulted early on, we’re probably going to lead first with TCHP, which would make the transition to postoperative less common.

The issue with the APHINITY data and how it leads into ExteNET is the majority of us would have given TCHP in the neoadjuvant setting. The APHINITY data are very helpful for us to understand, and we’re seeing the separation of the curve more at the 6-year follow-up than we did at the 3-year follow-up. But it’s not necessarily the same place that we would be in to make the decision about adjuvant neratinib, because those patients did not receive a full year of pertuzumab before benefiting from an additional year of a tyrosine kinase inhibitor.

My biggest struggle with the ExteNET data is just knowing that it followed a year of trastuzumab, not a year of trastuzumab-pertuzumab. I don’t know what that added additional benefit would be.

Adam Brufsky, MD, PhD: Let me ask you a question. The fact that the curves in APHINITY separate late, does that make you guys think that the triple-positive clones are probably driving this now? Usually with an ER [estrogen receptor]–negative/HER2-positive disease, someone is going to get their disease and relapse in 3 years or they’re not. When I start to see these late relapses, I think, “Oh, man, maybe it’s the triple-positive stuff.” Any comments on that from anybody? Virginia, what do you think?

Virginia Kaklamani, MD: I think you’re right. To Carey’s point, when you look at ExteNET, there was no or very little pertuzumab. There is no T-DM1 [trastuzumab, emtansine], and we’ll talk about that as well. But we’re always going to have gaps in data. We have to do the best we can with the gaps we have, because we’re not going to ever have a future ExteNET where patients get pertuzumab, get T-DM1, and then get randomized to neratinib versus not. I typically will give neratinib. My main concern is diarrhea. I know the control trial was just published, and we have data on what to do. But we still have pretty high numbers of grade 1 and 2 diarrhea, which for patients who have been on over a year of therapy, it’s pretty hard for them to tolerate.

Adam Brufsky, MD, PhD: Yeah, I agree. That’s the big issue. Although, there are some pretty good data. I don’t think it’s TCHP. I don’t think it’s ever been published, but Michael Gnant presented, I think at San Antonio Breast Cancer Symposium or ESMO [European Society for Medical Oncology Congress] in 2017, an analysis of people who had neoadjuvant—it was like 100 people. EXTENET was what, about 2500 people, 2000 people? I think 10% of them had neoadjuvant therapy, and he looked in the postneoadjuvant setting, and it did have substantial benefit to the people who have residual disease in the postneoadjuvant setting. It gives us something to think about in the way, as Carey was saying, we treat people like this. But I agree. The other thing is that if the people who are relapsing are the ones later on who are triple positives, that’s who the tyrosine kinase inhibitors are going for, right? This was where most of the benefit was. Mark, what do you think?

Mark D. Pegram, MD: For a high-risk patient, after stage III or IV disease or more positive lymph nodes at a young age, those are the patients where I think about adjuvant neratinib. Those patients may have already had both antibodies and postneoadjuvant T-DM1. But if they have stage III disease, if ExteNET is now FDA approved, I feel obliged to have a balanced discussion with those patients about the risks and toxicities. But in the wake of the controlled trial publication and the escalation of neratinib dosing early on to mitigate against lower GI [gastrointestinal] toxicity, it can be managed in very high-risk patients. In lower-risk patients, I don’t think the risk-benefit ratio is favorable for extended adjuvant neratinib.

Adam Brufsky, MD, PhD: Totally agree with you.

Transcript Edited for Clarity

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