DR PEREZ: We had the original data, demonstrating that adding a second anti-HER2 agent — so just pertuzumab — to docetaxel/trastuzumab significantly improved progression-free survival. And at San Antonio is the first time that we heard the presentation of the significant improvement in overall survival for this group of patients, with actually about 5% absolute difference in 1-year survival for the patients who received the triple drugs versus the 2 drugs. So very positive data.
Then there was the analysis of biomarkers in CLEOPATRA that really demonstrated 2 main things. First, there’s no differentiating biomarker between trastuzumab and pertuzumab, really. And number 2 was that there was an analysis of the potential impact of PI3 kinase mutations with outcome, demonstrating that for the overall group of patients with HER2-positive disease enrolled in this study, having PI3 kinase mutations was associated with worse outcome, although it did not differentiate between the use of trastuzumab alone versus trastuzumab plus pertuzumab. These results give impetus for the evaluation of PI3 kinase inhibitors in the setting of HER2-positive disease.
DR LOVE: Sara, globally, what do we know about markers predicting who responds or not to various anti-HER therapies?
DR HURVITZ: We have more theories than we have real evidence. There really is nothing that predicts who’s going to respond and who’s going to have de novo or acquired resistance. A lot of work’s been done on the PI3 kinase pathway. There are 2 studies, BOLERO-1 and 3, that are addressing inhibiting mTOR in patients with HER2-positive metastatic breast cancer in either the first-line setting or the trastuzumab-pretreated setting. So that will be addressed.
I think really the neoadjuvant setting is where we’re going to be able to query and address some of these questions that we have. There are a lot of studies — Neo-ALTTO and NEOSPHERE — where tissue acquisition was built into the study. My understanding is that these studies are not yet ongoing, that there are still decisions regarding how the tumor tissue will be used.
We actually have a 130-patient neoadjuvant clinical trial where patients are randomly assigned to receive TCH versus TCH plus lapatinib versus TC plus lapatinib — very similar design to Neo-ALTTO, much smaller study. The biomarker studies are ongoing right now as we’re doing the pathologic complete response rate analysis, and so we should have our data ready by next fall, which will be presented at the same time. And what’s interesting is we’ve been collaborating with Joan Brugge’s group at Harvard, who’s working with us on analyzing the tissue and looking at Bcl-2 expression as perhaps a pathway that gets upregulated and may predict resistance to the tyrosine kinase inhibitor.
DR LOVE: Hope, any comments about this issue of predicting responsiveness? Also, any thoughts about why it is that pertuzumab is adding so much to trastuzumab? I mean, we know the simplified explanation, so to speak, in terms of dimerization. But any further thoughts you have about what’s actually going on? Is the immune system in some way involved, for example?
DR RUGO: Two easy questions. The search for predictive markers has been a very difficult one and elusive. Today we are no farther ahead than we were when we first found HER2. We know that we can predict response by hormone receptors, primarily ER and HER2, and a little bit about tumor biology that we normally look at — grade, for example. But other than that, we have markers that have turned out to be prognostic — for example, potentially, activation of the PI3 kinase pathway, but not predictive markers. The one thing we did hear recently, which was interesting but I don’t know where it will go, is a little bit of a difference in immune markers from NEOSPHERE.
In terms of why pertuzumab works, great question. I think the ADCC or the immune effect of both trastuzumab and pertuzumab are really important for their mechanisms of action. And there’s clearly a synergistic effect that may not be well demonstrated in preclinical models or demonstrable in cartoons that happens when you give both antibodies. You block two things together and it’s much better than one. Why pertuzumab by itself is not as effective may have to do with how we’ve been testing it, which is in patients who’ve already progressed on trastuzumab, and other mechanisms, which we don’t understand very well.
DR LOVE: Lisa, what’s your take on this? And in terms of looking, Hope said we have a lot of tumor. Is it possible that maybe that’s not really where the answer is, the tumor, but more in the host?
DR CAREY: I think the study that Hope was just alluding to was presented by Luca Gianni, where they looked specifically at immune mechanisms, which presumably, as we know — some of these immune mechanisms come from the tumor and some come from the microenvironment. PDL1 and CTLA4, which are both targetable, both were associated in multivariate analyses — which were incredibly complicated, so we have to take them with a grain of salt — with residual disease. Theoretically, that means that tumors do overexpress these things and you do have adaptive immune resistance mechanisms that have been demonstrated preclinically. It looks like we may actually start to see this in vivo, in people.
If you can target it, that may actually be a therapeutic strategy, and that would be very relevant to know about, because these drugs — of course, we all read the New England Journal papers about targeting PD1 and PDL1. Those were not in breast cancers, but if the mechanism’s intact, the mechanism is intact.
DR LOVE: Edith?
DR PEREZ: The third issue was to expand a little bit on the immune data presented because this presentation in San Antonio by Luca was actually not a mechanistic evaluation, but they looked at known immune gene signatures. Then they attempted to correlate the outcome of patients with this signature. So a different way than the way we’re looking at this. But I think there’s a need for further studies of the immune system as part of the mechanism of action in these antibodies. And we are actually conducting a study right now, a prospective study, in which we’re collecting blood before and during anti-HER2 therapies, looking at T-cell function and ADCC to see if we can figure this out.