Trastuzumab Deruxtecan in the Neoadjuvant Setting

Dr. Charles Geyer: I guess one other thing, one other abstract that I'm just thinking about that I thought was, again, informative for the idea that HER2-low patients, different populations, I think one nice way to look for that would be to see, "Well, do they respond differently to standard chemotherapy drugs in some form?" If maybe they do, then maybe there is something, but if it doesn't look like the HER2-low/zero status has impact with our conventional agents, probably it's more related to just the extraordinary delivery of drug that we see with T-DXd than a fundamental biologic difference. And they did that with RxPONDER, they went back and looked to see if HER2-low/zero had any impact, and it did not. So I think that was a nice quick check for just another bit of information, the genomic studies are very elegant, but I think it's nice to go back to clinical data and just look for things like this. I thought that was a nice poster that in my mind reinforced it. This is much more just about the amazing ability of ADCs to deliver more effective therapy without ratcheting up toxicity. So to me, I think this is really exciting, we are clearly in the era of the ADCs, and we just now have to figure out how to optimize their use in patients with metastatic disease, and of course, moving up into the early setting. I guess it was interesting in the early setting to see the preliminary results of a TALENT study, T-DXd has just been impressively positive, every study that we've seen since you presented the phase one data at San Antonio. And the TALENT study wasn't all that impressive, I didn't think. What were your thoughts on it?

Dr. Ian Krop: Yeah, so just for everybody, this was a neoadjuvant trial looking at patients with HER2-low, hormone receptor-positive disease, so this is actually the first neoadjuvant data we have on T-DXd, as far as I know. And we know, in general, that hormone receptor-positive patients treated with neoadjuvant chemo, the conventional chemotherapy, have a pretty low pathologic complete response rate, 10% or somewhere around there. So, we know that conventional chemotherapy is not highly active in that patient population, and the question with this TALENT trial was, given the potency of T-DXd and the ability of ADCs to, as Chuck said, to specifically deliver this cytotoxic to the cancer cell, would it have a different impact on these ER-positive early-stage cancers than conventional chemotherapy? And this was a small study, it looked at patients- it gave either T-DXd or T-DXd plus anastrozole, and it's a small study, the full dataset is not yet available. There was some activity, there were a small number of pathologic complete responses and some near pathologic complete responses, but my general sense is this didn't look like it was a game changing result. And I think the authors, should be commended for doing this trial. And clearly, the drug did appear active there, it just didn't look much different, I think, than what we would expect with conventional multi-agent chemotherapy. But, again, we'll see as they finish, as they're able to get all of their response data completed over time, we'll have a better picture onto this question, but at least so far, it shows some activity, but not much different than what you might expect with chemotherapy.

Dr. Charles Geyer: Yeah, I think there was understandable optimism or hope, that as you said, maybe this drug could change that very low PCR rate and basically perform about the way most of our combination chemo drugs. So I think the idea that maybe we can just replace their chemo altogether, I think we're going to need to definitely look at the drug in early breast cancers, but it doesn't look like it, at least at this first blush that it's going to get all the way to PCR, of course. We're so impressed with the response rate and metastatic disease, that just means the evident tumor is no longer there, we know there's still a tumor. So this was a higher bar to clear for the drug, but I just thought it was interesting, because everything we've ever seen, you're just blown away by it. So this was the first, what I call, a study that made us pause, at least.

Dr. Ian Krop: Yeah. More to come there. And again, there's certainly other ADC studies in the early stage setting that they're being looked at. Sacituzumab Govitecan also has been looked at in the neoadjuvant setting, and clearly, again, active but not dramatically different than what you would expect with chemotherapy. So maybe, I think the next question would be, "What about in the HER2-positive patients? What's T-DXd going to do in the new adjuvant setting in the HER2-positive patients?" And there are studies asking that question, that we'll read out soon, so we'll get some information from that as well. But yeah I think we had almost a whole day of San Antonio devoted to antibody drug conjugates, it's clearly an area that's had tremendous impact and is going to continue to have that, and how we use these drugs now that there's- in the HER2-positive space I think it's now pretty clear. I think in the HER2-low and ER-positive patients and triple negative patients, how you sequence the various different ADC which have overlapping populations with Sacituzumab Govitecan and trastuzumab Deruxtecan in the HER2-low and ER-positive versus just ER-positive in general, where we know Sacituzumab has activity. And similarly, with the triple negatives, where both drugs are- or the HER2-low triple negative versus where we know T-DXd has activity, we also know Sacituzumab is quite active there. How we're going to deal with those overlapping populations, I think, is a little complicated and we just don't have good data because we don't have head-to-head comparisons. And then, of course, the question of, if someone progresses on TDM. We now know if somebody progresses on TDM-1, that the T-DXd is still very active. We don't know the converse of that. We don't know if somebody progresses on Sacituzumab whether switching to a HER2-targeted drug will be beneficial. So those ADC after ADC questions also need to be evaluated, and there's some trials getting underway looking at that. But certainly it's a good thing for patients that we have this whole new class of drug, but whenever we have a whole new class, we now need to figure out how best to use them, and that's where I think we are right now, awaiting some data.