Trials That Shaped HER2-Positive Therapy for BC

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Joyce A. O’Shaughnessy, MD: Thank you all very much. Let’s transition now to HER2-positive disease. Sara, you could start up. We’re talking about some of the data sets that have brought us to where we are today.

Sara A. Hurvitz, MD: Absolutely. We’re going to focus primarily in the early stage neoadjuvant and adjuvant setting, at least initially. It was a few years ago now that ExteNET came out and we had these data showing about a 2.5% improvement in invasive disease-free survival in higher-risk HER2-positive breast cancer. Based on subgroup, there was some indication that perhaps it was the ER [estrogen receptor] co-expressing in lymph node-positives that were deriving benefit from this pan-HER inhibitor. Of course, the adverse effect that’s so concerning is grade 3 diarrhea. The rate is quite high, and to give a woman a whole year of extended therapy after completing her year of adjuvant trastuzumab, I think all of us in the clinic actually have to look at the patient and say, “Are you high enough risk to derive the benefit and make it worth this relatively quality-of-life-impairing adverse effect of diarrhea?"

That did become available. The FDA approved it…it still isn’t approved for metastatic disease. We received the data relating to APHINITY and the use of a year of pertuzumab in the adjuvant setting. Again, it was a statistically significant finding. There was about a 1.5% improvement in 3-year invasive disease-free survival. These were not patients who had been treated in the neoadjuvant setting, so they weren’t selected for that sort of high-risk residual disease. The statistical significance was met with a hazard radio on the order of 0.8, and it did lead to FDA approval, which made a lot of us scratch our heads, because now we’re obligated to discuss these data with our patients.

From a cost—and I mean cost, not just financial, but toxicity—point of view, versus absolute benefit for the patient sitting in front of us, I only feel that it’s right to give this to patients who are very high-risk node-positive. We don’t know what to do with the patients who get a full year of trastuzumab/pertuzumab. Do we then go on and give them neratinib? The neratinib study didn’t include pertuzumab. I felt really happy when recently the KATHERINE data came out, because now, again, we’re spoiled with a nice, chunky improvement in the outcomes. The debate has become a little less relevant about slicing and dicing the absolute risk reduction.

Joyce A. O’Shaughnessy, MD: On that note, Debu, tell us about the KATHERINE trial.

Debu Tripathy, MD: The KATHERINE trial, as Sara pointed out, is very important, because it gives us the paradigm that neoadjuvant therapy is a bioassay. For your higher-risk patients, those who are above clinical stage I, neoadjuvant therapy allows us to identify those patients who were eligible for the KATHERINE study—those that end up having residual disease, even a small amount of residual invasive disease. Those patients were randomized to completing maintenance therapy with either trastuzumab or T-DM1 [trastuzumab emtansine], and it showed a 50% hazard ratio in terms of recurrence. That’s a big number, and it translates into significant absolute disease-free survival outcomes. The toxicities are higher. You have a higher rate of discontinuation due to [adverse] effects and hematologic adverse effects.

Still, it is an important step for us to learn from. I think more and more, certainly in triple-negative, we’ve been doing this. We’re going to be learning that response to therapy actually helps us make a treatment decision. We’ve thought about that for many years with neoadjuvant therapy. This is the first proof that we can actually do it, apart from the CREATE-X, for triple-negative. This is an important step forward.

Erika P. Hamilton, MD: To echo your point again, it’s important to give these patients neoadjuvant therapy so we have that ability to risk stratify them, right?

Joyce A. O’Shaughnessy, MD: Yes. It’s a new standard of care now, even with a small amount of disease left. If you’re not a full pathologic complete response in breast and lymph node, it’s a new standard of care—FDA-approved, guideline sanctioned, etcetera. It’s because a hazard ratio of 0.5 is so dramatic, basically. I’m going to admit that, having done all of that for a high-risk individual who starts off quite node-positive, she’s ER-positive, less likely to have a path CR [pathologic complete response]. We optimize endocrine therapy for her, finish up her year of T-DM1, and do radiation therapy. You know what? I am still having a conversation about neratinib, because I feel like its mechanism of action is non-cross-resistant. The interplay between the estrogen receptor and the HER family is fascinating in ExteNET, because after 1 year of neratinib and stopping, the curves continue to split apart for the ER-positive patients.

The diarrhea has to be aggressively, proactively managed for the first for the first month or two, right? After that, it’s been relatively more mild, but you’ve done a lot of work on this, Debu.

Debu Tripathy, MD: Yes, we’re running the CONTROL study, which is specifically dedicated to controlling diarrhea for adjuvant neratinib. A 70% incidence of grade 3 diarrhea was seen in the ExteNET study and, as you mentioned, concentrated in the first 2 months. A variety of maneuvers have been done. Colestipol seems to be the most effective, but what really helps us is slowly escalating the dose of neratinib until you get to the full dose, and using loperamide as needed. You don’t want to use it automatically, because constipation is actually a problem. In fact, that was one of the main toxicities. About a third of the patients had that as a problem. I do think it can be managed carefully. The discontinuation rates are still high, but to the point you made earlier, if you look at the data from the KATHERINE study, recurrences are still happening in the group that got T-DM1. Having residual disease is truly a high-risk factor.

Joyce A. O’Shaughnessy, MD: Yes, thanks for that. The CONTROL trial has given us a lot of good…. There was an amendment to the CONTROL trial—correct me because you’re the investigator—starting at a lower dose, 120 mg, which is 3 pills, going up to 160 mg after a couple weeks, and then I go to 200 mg next. They went right from 160 mg to 240 mg, stepping up every 2 weeks by adding another pill, and stopping if somebody was having trouble.

Debu Tripathy, MD: Right.

Joyce A. O’Shaughnessy, MD: Lung cancer doctors do that with afatinib. I’ve had some luck with that, but aren’t there some preliminary data showing that it looks like it might help?

Debu Tripathy, MD: Yes, that was the dose escalation scheme I was referring to earlier. That one is without all of the other antidiarrheals, other than loperamide as needed.

Transcript Edited for Clarity

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