DR HURVITZ: So our study was a little bit larger. We had a 444-patient Phase III clinical trial, which was evaluating T-DM1 plus pertuzumab for 6 cycles prior to surgery versus TCHP, docetaxel/carboplatin/trastuzumab/pertuzumab, for 6 cycles, followed by surgery. There was biomarker-based biopsy done baseline and then after cycle 1. And the pathologic complete response rate in the breast and lymph nodes is what was presented at ASCO this year.

And 56% of patients who received TCHP achieved a path CR in breast and lymph nodes compared to 44% with the T-DM1. So it’s not what we expected. We thought T-DM1/pertuzumab would do just as well. We were really hoping for that from the patient perspective, given the relative lack of toxicity, which we also showed in our data set at ASCO.

But it is kind of interesting to look at it from another perspective. Forty-four percent of patients went through nontraditional chemo and had no disease left at the time of surgery. And can we figure out who those patients are and how to predict that sort of response so that we can avoid the use of transitional chemo in some of our patients?

DR LOVE: And, of course, I guess the other question is, is pertuzumab adding anything? Because those numbers, 44%, I don’t think is that much different from the limited data we have of just T-DM1 alone.

DR HURVITZ: You’re absolutely right. Nadia Harbeck presented the ADAPT study. And that was actually just in HER2-positive, ER-positive. And with T-DM1 alone, she had about a 41% path CR rate with T-DM1 alone. And adding endocrine therapy didn’t improve that. So I think that these results are kind of neck and neck with her study there, even though her study was restricted to hormone receptor-positive.

So I agree with you. I don't know what pertuzumab is adding. The original study design of KRISTINE was a 5-arm study where the “S” in the KRISTINE was a 5. And it was reduced down to a 2-arm study, and so that interesting question was not able to be addressed due to limitations in our design.

DR LOVE: And, of course, we had seen previously in metastatic disease the MARIANNE study, where pertuzumab didn’t add very much to T-DM1. Taking a step back and thinking about how you think pertuzumab is working and helping, any explanation for why it doesn’t seem to help with T-DM1?

DR HURVITZ: I don’t know, but I am underwhelmed by the data from MARIANNE in comparison to the ADAPT study. Preclinical models suggest that trastuzumab and pertuzumab are synergistic. And the CLEOPATRA data is pretty overwhelmingly positive, where the addition of trastuzumab to pertuzumab really improves long-term survival. But with T-DM1 it doesn’t, in the clinical setting, appear to add much. And so it’s something that I can’t really speculate on much further.

What I’m hoping is the biomarker data that we have from the serial biopsies done in this trial will begin to address some of the questions. I guess we don’t have an arm where patients only receive T-DM1, but we’ll be able to at least start looking at what pathways are involved in resistance.

DR LOVE: It kind of also ties into a basic question that, I don't know, people don’t seem to ask too much, which is, why does pertuzumab help so much when you add it to chemo/trastuzumab? I mean, that huge bump in the CLEOPATRA trial. And for simple people like me, yes, we can look and say, “Okay. It’s blocking something else.” But what does it really mean? I mean, do you think this could be immune based?

DR HURVITZ: It could be immune based. I mean, I still think that it’s the blockade of signaling and the PI3 kinase pathway is where the impact is. I’m still not totally convinced that the data we see with trastuzumab and/or pertuzumab is due to increased ADCC. We’ll have to see more data in that realm. I know that molecules are being developed that bind the FC receptor more strongly and may be a proof of concept for that. But I think it has to do with signaling.

And I talk with colleagues of mine, and we are somewhat perplexed and scratch our head over the CLEOPATRA data because it is so outstanding. And it would be nice to see another study confirm that, keeping in mind that 90% of the patients in CLEOPATRA were naïve to trastuzumab. So they’d never seen it in the adjuvant or neoadjuvant setting. Is there something about the patient population that made it so dramatically different?

Genomic assays and (neo)adjuvant treatment decision-making

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Management of metastatic breast cancer (mBC)

CDK4/6 inhibitors for the treatment of breast cancer

Checkpoint inhibitors and other novel immunotherapeutic approaches to breast cancer

Triple-negative and BRCA mutation-positive breast cancers