Harold Burstein, MD, PhD, and Guilherme Nader Marta, MD, discuss the DESTINY-Breast11 and DESTINY-Breast05 trials examining trastuzumab deruxtecan in HER2-positive breast cancer.
We're continuing our discussion of highlights in breast cancer from ESO 2025 held in Berlin this year. Certainly one of the sets of highlights were the new data for the use of trastuzumaboxican or TDXD in early stage breast cancer with two really important studies, and I'm delighted to be joined. Guillerme Neder Marta, one of our international scholars who's with us today from Brazil to be talking about what these data are and what they mean for clinical practice. So let's start with DB 11. This was a neoadjuvant study for HER2 positive breast cancer. Tell us a little bit about how this study evolved. So, DB11 was a phase 3 international trial that enrolled patients with high-risk early stage breast cancer that had not received any prior, uh, therapies, and patients were actually randomizing this study uh for one of three arms. The control arm was ACTHB, so anthraccycline containing regimen. Uh, there was another arm with TDXD for 4 cycles followed by Taane tratuzumab, and Pertuzumab, and there was actually a third arm, which was 8 cycles only with the ABC of TDXD. The third arm of TDSD only was actually discontinued early on because of the independent data monitoring committee uh saw some concerns about lower rates of PCR in this in this in this arm. So TDXD monotherapy is not going to be a player in the longer term results here for this. It doesn't look like it's gonna be. So tell us just a little more about the patient population here, which kind of patients went on to this study? So this, this study actually enrolled a high risk patient population, uh, in order to be enrolled in this trial, patients would have to be at least a T3 tumor, uh, with any not of status or Uh no positive tumor and the important aspect here is also that patients with inflammatory breast cancer were allowed in the study. They were well represented in the trial. That's a nice point because a lot of times clinical trials exclude inflammatory breast cancer patients because of the high risk nature of that disease. So what was the primary endpoint and what did we learn in this trial? So the primary endpoint of the study was uh PCR, and we have seen some remarkable results with an improvement of 11% in the PCR rate. Uh, favoring the TDXD THBR in comparison with the ACTHBR, which was really, uh, significant in deciding. So this past year at ASCO, we saw a whole bunch of studies that looked at THP as the regimen for neoadjuvant therapy, and we were seeing uh PCR rates there in the range of 40 to 45%. We're now talking about 67% here, so that seems like a pretty big improvement with the. Addition of the TDXD before THP, you agree that this looks meaningful? I agree that looks very, uh, meaningful, statistically meaningful and also clinically significant to me. Uh, it does looks like an improvement compared to our, uh, current, uh, previous standards. So it's really something that I found very interesting to observe. So let's um come back to the discussion at the end about where this fits, but move on now to the other trial of TDXD in the early stage setting. So this was the Destiny Breast 05 trial, which looked at patients who had residual tumor after standard neoadjuvant therapy. Tell us about the patients who went on to this trial. So this trial of Destiny Breast 05, was also a randomized phase 3 trial international study. Uh, that actually included a very high risk patient population, so patients would have to, would, would need to have either any uh inoperable tumor at baseline prior to any, uh, therapy, or would have to, uh, after a new adjuvant therapy to have a node positive residual disease. So these are, as you say. Very high risk group, not your typical patient who might come in with a 3 centimeter HER2 positive cancer, get a standard neoadjuvant regimen, and have some residual disease in the breast but not in the lymph nodes. This is a much higher risk group than that. Absolutely, and I think that's a very important point when we interpret these results and we sort of start thinking which patient populations are going to be uh better for each of these uh strategies that we're seeing. So the control arm here was TDM1 and of course that had emerged in the Catherine study where patients who similarly had residual disease were offered either continuing trastuzumab-based treatment or TDM1. What was the schema here in the DBO5? In DBO-5 actually patients were randomized for in the post-operative setting to receive 4. cycles of either TDM1 as was done in the Catherine trial or the the intervention arm which was TDXD for the same duration of uh 14 cycles. So 14 cycles here and just remind me in the DBO11 study, how many cycles of TDXD did they get? Was it 4 or 64, so a much longer course of TDXD treatment here in in that setting. So the primary endpoint here was disease-free survival. What did we learn? So, in this, in this study, we already saw the, the results of the primary endpoint, which was invasive disease-free survival, and we have the, the, the results that were presented showed us that there was actually an improvement uh in the rates of invasive disease-free survival with a reduction of 50, almost 50% reduction. In the risk of invasive recurrence or death, uh, in this, with favoring the, the intervention arm with TDXD and that resulted in a three-year improvement of almost 9 to 10%. Of NDFS at 3 years, so we need significant results as well. I agree actually. I thought these were some of the most practiced defining data to emerge at the meeting because it is a reasonably high risk group and to me it seems like a pretty rational use of TDXD in the space and we already see in the metastatic setting that TDXD was associated with a better progression free survival or tumor control, if you will, than TDM-1 in the second line. So let's try and sort of put all this together. First, TDXD has climbed the ladder, right? It started a refractory HER2 positive disease. Now we, then we had data from DBO3 and the second line. DBO-9 was presented earlier this year in first line metastatic disease. Now it's leapfrogged into early stage. Is this game over for? anti-HER2 treatments, is this as good as we're going to get and it's just a matter of figuring out where to deploy the drug. I agree these are very remarkable results we're seeing of this drug. We haven't, we have had advances in the further treatment of HER2 positive breast cancer, but we haven't seen before a drug that would have significant impact. Across all these different settings. TDM one, for example, didn't, uh, was not better than first line THP so we are, it's really remarkable to see this, uh, the all these positive results from important trials. Having said that, uh, there are some signals that this drug is not gonna solve all our problems. We have just seen that the TDXD only arm. Uh, in the, in the nowman trial did not, uh, have as good results as the combination arms. Uh, for the first line sighting, we are yet to see the results of the, the TDXD only arm. We have seen the results of the TDXD combined with Pertuzumab. Uh, and there is, there is interest also in uh some potential combinations, for example, with, uh, gerozine kenazine inhibitors that may perhaps even improve even further our outcomes. Sounds like there's more to learn. Let me just ask you a final couple of questions. Um, one is, were you satisfied by the control arm of the DBL? And study and in particular the role of anthraccycline still it's been a long time since I gave anybody an anthrocycline for HER2 positive disease in the neoadjuvant setting. Do you think they missed a chance to look at TCHP or are you satisfied that we know what we need to know here? So I think we can split the answer to this question in two parts, in terms of efficacy, we have all, as you said, have been. See the intracycline free regimen especially CHP as probably an equally effective therapy for early stage uh HER2 positive breast cancer. So in terms of the the comparison for efficacy, I am satisfied that with the ACTHP I think it's very unlikely that the TCHP would be significantly better, uh, so I think that's a fair comparison. But having said that, we, we're not looking here only at efficacy. We're only the the other very interesting finding from, from this study was that the the TDXD containing arm also was safer, had lower rates of grade 3 and serious adverse events, and in that aspect, I think it would be very useful for us if we had had the chance to compare TDXD THP with our most current standard TCHP. So we've been talking about trastuzumab drotican or TDXD in the management of early stage HER2 positive breast cancer. It completes a remarkable run up the ladder from refractory metastatic disease to first line metastatic disease and then into the early stage space with clinically important data from the ESO 2025 meeting. Thanks so much for joining us. Thank you for having me.
