DR MAMOUNAS: I think the thinking behind it is that the FDA recognized that the significance of pathologic complete response in terms of the surrogate endpoint for outcome and also recognized the importance of not having to wait for many years for new agents to come to the patients. So the neoadjuvant setting provided this opportunity to potentially approve drugs in an accelerated fashion, make them available for patients until we get the long-term data.

Obviously, the guidelines suggest that there has to be a robust increase in pathologic complete response before such an approval is given and also that there will be data on disease-free and overall survival that will be coming on from either large neoadjuvant trials or large adjuvant trials. And pertuzumab fell into that category. They already had completed the adjuvant trial. They had 2 small but yet randomized trials of neoadjuvant therapy showing increase in pathologic response, although the second one, as I mentioned, they had pertuzumab in all arms, but certainly the pathologic response rates were significant magnitude. So that met the criteria.

And the idea behind it is that only a large increase in pathologic complete response would potentially translate into survival benefit. A small increase in pathologic response in the range of 5% to 10% is very unlikely to increase disease-free or overall survival.

DR LOVE: And I guess they point out that the path CR rate, when you add pertuzumab, was 39% compared to 21% without it, so almost a doubling.

But Kim, it also kind of says, “We’re expecting this to play out in the adjuvant setting. If it doesn’t, we’re taking back the approval,” but then people have looked at this and said, “If that’s the case, why can’t we give it adjuvantly?”

And, in fact, the NCCN has a statement in there saying that maybe that could be done. Can you talk about that?

DR BLACKWELL: Yes. The NCCN basically says it should be considered. And the reality is that for patients facing HER2-positive breast cancer, from the closing of AFFINITY until we see the AFFINITY data, there’s really no other trial that these patients can participate in. And given the survival benefit in the metastatic setting and, more importantly — and I think Terry touched upon it — but it’s the most important thing to me, is that we have a very good safety database about adding pertuzumab to chemo. This is a very safe drug. It has a very high therapeutic index. So the reality is, we have that safety data.

And this is my perspective, is that we shouldn’t penalize the patient just because they had surgery first. And in this period of time, it is a very reasonable thing to consider giving pertuzumab in the adjuvant setting for patients who, unfortunately, didn’t have an opportunity to meet with a medical oncologist prior to their surgery.

DR LOVE: So you do that? Have you been able to do that?

DR BLACKWELL: I’ve been able to do it, and I, in all honesty, I think that the potential benefits outweigh the potential risk.

DR LOVE: Although the issue is that, theoretically, pertuzumab is only approved in the neoadjuvant setting right now. People are trying to use it, citing the NCCN. Any sense about how easy or difficult it is and how many oncologists are actually following through and doing this?

DR BLACKWELL: Everything we do in oncology in getting things approved has some certainly level of difficulty. I guess the example that I always use when people say, “It’s only approved for this,” 80%, maybe even closer to 90%, of what we do in medical oncology every day doesn’t carry with it a formal FDA approval. And those are things that have a much lower therapeutic index, giving an anthracycline, for instance, or giving a taxane weekly as opposed to — I mean, these are things that aren’t formally approved but have been shown to not only be safe but also have a potential benefit for the patients facing breast cancer.

And even when we had adjuvant trastuzumab approval, we easily extrapolated that, especially in the locally advanced breast cancer setting, to the neoadjuvant setting. Trastuzumab is not formally approved in the neoadjuvant setting, and yet we use it all the time because we think it offers patients benefit. In fact, none of the drugs we use are approved in the neoadjuvant setting formally, but the reality is, we use them because we believe. And so why wouldn’t the converse be true, which is that we have good data in the metastatic, we have good data in the neoadjuvant setting and that there’s at least a high enough potential that there would be a benefit in the adjuvant setting, in my mind, in the absence of a safety signal, that I feel very comfortable utilizing pertuzumab in the adjuvant setting.

Local disease control and neoadjuvant treatment

Neoadjuvant treatment of HER2-positive tumors

Neoadjuvant treatment of triple-negative tumors

Neoadjuvant treatment of ER-positive, HER2-negative tumors

Other issues in neoadjuvant treatment