Adjuvant Therapy for HER2-Driven Breast Cancer

Transcript:Adam M. Brufsky, MD, PhD: We’re now going to turn to the HER2 space, and we’re going to start with adjuvant therapy. At this year’s ASCO meeting, we’re going to see the first results from the APHINITY trial, which is adding pertuzumab to trastuzumab-containing regimens as adjuvant therapy for early stage HER2-positive breast cancer. José, I believe you were the PI of the steering committee. Do you want to talk about that trial?

José Baselga, MD, PhD: Sure, absolutely. This is a large study: It has over 4000 patients. We met its primary endpoint, an improvement in iDFS that was significant and had a powerful hazard ratio. What we also are learning in these trials is that the control arms, the arms who receive Herceptin and chemotherapy alone, perform better than they historically have.

So, if you look at the APHINITY trial and the ALTTO trial set, patients who received the control arm did better compared with historical patients. It’s not going to be for everyone. I think that we will need to identify those patients who have a high risk, or higher risk, of recurrence, and they will clearly benefit. The discussion is not going to be on whether or not to use it, in my mind, but rather in whom to use it—and it is really based on risk factors that are common, such as node positivity or ER status, and then hopefully in other biomarkers of HER2 dependency that we’ll need to identify.

Adam M. Brufsky, MD, PhD: It’s interesting because everybody is using at least ACTHP (adriamycin, cyclophosphamide, paclitaxel, trastuzumab, pertuzumab) or TCHP (docetaxel, carboplatin, trastuzumab, pertuzumab) right now in the neoadjuvant setting. All the APHINITY trial is doing is adding another 11 doses of pertuzumab. Is it going to change practice? Kim, is it going to change your practice?

Kimberly L. Blackwell, MD: Probably not. At least from what I understand of the results that are available to date from the APHINITY trial, there’s a large percentage of patients facing HER2-positive, early-stage breast cancer who are going to present with node-positive disease and are going to present with ER-negative disease. And those are the patients for whom I will certainly continue to do what I’ve been doing, which is a full year of pertuzumab. I use TCHP a lot in the preoperative setting, and then I’ll continue it in the adjuvant setting. In fact, I think this will only increase my use in that setting because it probably will get insurance coverage based on the positive end point.

Adam M. Brufsky, MD, PhD: Any other comments? Denise, Debu?

Denise A. Yardley, MD: I think, as we start seeing these adjuvant trials—our control-arm patients are doing so well, and I think when we take and extrapolate these subgroups, those are the ones whom we’re going to apply these agents to because a good majority of the patients are doing well without all the additional therapies. And so—as Kim was just saying—I think those subgroups who are really most likely to derive the benefit are the ones whom I’ll be looking at for extending it. I think it’s easier because it’s given concurrently with Herceptin versus something like neratinib.

Adam M. Brufsky, MD, PhD: Right. It’s not really doing anything different. It’s just additional cost and 21 minutes of infusion, a half hour more of infusion.

Debu Tripathy, MD: I think there’s something unique about antibody therapy because the antibodies in the HER2 space and just in general in breast cancer have been the ones that have had the biggest impact on survival in the metastatic setting. It could be an immunological reason, and I think it’s really impressive that the addition of pertuzumab in the metastatic setting gave you a survival hazard rate of 0.6, in the mid-0.6s. That’s a pretty strong effect, so I think this is a big deal.

It’s hard to say how this is going to play out and how many lives it’s going to save as we start getting really long-term data, but I think it’s a big step forward when you look at all the big steps we’ve taken in breast cancer advancements. I think the improving adjuvant therapy, where you clearly have an improvement in the cure rate—that’s important.

Adam M. Brufsky, MD, PhD: Are there any concerns about pertuzumab toxicity? Have you seen more diarrhea?

José Baselga, MD, PhD: We have seen a little bit more diarrhea, but it’s self-limited. It’s not very severe. It’s a very clean compound. We learned this from the CLEOPATRA trial. We have not seen any additional signals. The population group that perhaps we’ll need to pay more attention to is the elderly, so the elderly patients have more diarrhea. But, otherwise, it’s pretty clean. No cardiac effects. The rash is minimal compared with everolimus.

Kimberly L. Blackwell, MD: Yes, and I’d say be careful about what you’re blaming the diarrhea on, especially if you’re giving the TCHP regimen. I’m consistently impressed because I think we’re really cautioning patients about the diarrhea, and then they get it and then we all freak out and stop the pertuzumab, and they still have diarrhea. So, I think you have to just be careful and understand that there are lots of things during this period that can cause diarrhea.

Debu Tripathy, MD: Let me throw out a question for all of you, then. Do you think carboplatin is needed?

José Baselga, MD, PhD: No.

Adam M. Brufsky, MD, PhD: No. In fact, it’s the first thing I’ll drop from a patient on TCHP if they have trouble. Either reduce the dose or drop it.

José Baselga, MD, PhD: I agree.

Adam M. Brufsky, MD, PhD: That’s the first thing I usually do with TCHP.

Carlos L. Arteaga, MD: Although, in the randomized metastatic study, there was a comparison between…

Adam M. Brufsky, MD, PhD: TH (paclitaxel and trastuzumab) and TCH (Taxotere, carboplatin, Herceptin).

Carlos L. Arteaga, MD: Yes, but it wasn’t straight. In the control arm, it was 100, and in the other, 75.

José Baselga, MD, PhD: But I think that Kimberly has a very good point on the issue of the adjuvant data set. I’m talking about how the TCHP subgroup is the one that has more diarrhea, and this is something that you need to take into account.

Carlos L. Arteaga, MD: I have a comment—a question, really. Maybe José, you can answer it. What does the use of neoadjuvant trials do to predict adjuvant trials? Is this another positive check on the list?

José Baselga, MD, PhD: I think so because if you look at the NeoSphere trial that the FDA approved based on pCR as an indicator of long-term benefit, this is the trial that confirms, indeed, that there is a correlation between pCR and disease-free survival. Now, in the area of lapatinib, it has been much more complicated. I think that it’s difficult to interpret, but this is a clean comparison. So, I think that there is clearly, in the HER2-positive space, a correlation between complete pathological response and DFS. I think there is.

Carlos L. Arteaga, MD: Personally, I think that lapatinib doesn’t pair up with pertuzumab pharmacologically, mechanistically. It’s just a weak HER2 inhibitor.

Adam M. Brufsky, MD, PhD: Yes. We have better HER2 inhibitors coming out.

José Baselga, MD, PhD: Can I make one comment to a point that Kim was making that I think is very important? I think one piece of advice we need to take into account that she mentioned, which is very important, is that patients on pertuzumab, when they have diarrhea, can have diarrhea because of something else. I had that example in my clinic very recently. A patient of mine who was on adjuvant pertuzumab and Herceptin began to develop diarrhea. It was severe, and I stopped pertuzumab, but the diarrhea went on and on and on. The patient had new-onset celiac disease.

Adam M. Brufsky, MD, PhD: Really? Wow.

José Baselga, MD, PhD: I had delayed the whole workup for at least 2.5 months because they said that it was pertuzumab, and it was not.

Kimberly L. Blackwell, MD: I think the other clinical pearl is that the drug does stick around. I’ve seen clinicians who have stopped it, and the symptoms don’t clear up after about 2 days, and then they restart the pertuzumab with the next cycle. So, the half-life of these antibodies is quite long, and I’ve had patients who come to see me for a second opinion who say, “Should I continue on the pertuzumab or not?” And the reality is that it takes a while to recover, if in fact it is the pertuzumab causing the diarrhea.

Transcript Edited for Clarity