Harold Burstein, MD, PhD, and Ana Garrido- Castro, MD, discuss the ASCENT-03 and TROPION-Breast02 trials, investigating antibody-drug conjugates for triple-negative breast cance r.
One of the highlights at ESO 2025 were updates and new data on antibody drug conjugates, a class of drugs that is taking the world by storm, particularly in advanced breast cancer. Here, I'm discussing it with Antica Rita Castro, who leads our research program in triple negative breast cancer. You were involved in several of these studies. You were the discussant for some of the key ones, so you know all the data and uh have all the perspective. Let's start with the ascent 03 trial. This was a study of Satuzumab Gova TA versus standard of care and triple negative disease. How's it different from some of the other work already with this drug there? That's a great question. So certainly some very exciting data for the TROP 280Cs at ESO. We know that Saituzumab Govitikan is currently approved for. Patients with previously treated metastatic TABC, so after progression on at least two prior lines of therapy, at least one of those for metastatic disease. Ascento 3 is looking specifically at situumab go TCA in the first line setting for patients who are not candidates for an immune checkpoint inhibitor in that space. So what were the key criteria for not being a candidate for an immune checkpoint inhibitor? So primarily, uh, PDL1 negative status and in ascento 3 more than. 99% of patients had PDL1 negative tumors. However, if patients had a PDL1 positive tumor but had received prior immune checkpoint inhibitor in the early stage setting or had a comorbidity that precluded use of immune checkpoint inhibition, they could have also been potentially eligible for the trial. Earlier this year we saw the Ascento 4 data, of course, which looked at stuzumab in combination with pembrolizumab, so we know what it did already in the PDL1 positive tumors, I suppose. So here's the schema. um, what were the standard, uh, options the patient could choose from? Yes, so in this study, patients were randomized to receive either situumab, Govitikin or chemotherapy physician's choice, which could have been either ataxan, Paclitaxel, not Paclitaxel, or double itt chemotherapy with carboplatin plus gemcitamine. I think one of the very important eligibility criteria for this trial was that patients had to have a disease-free interval. From treatment in the curative setting of at least 6 months or more, which is an important distinction compared to tropium breast 2, which we'll talk about in a minute. So the immediate progressors wouldn't be eligible, presumably the patients who got a taxane-based regimen were either further removed from taxing or never had treatment in the adjuvant setting or neoadjuvant setting, uh, same as what we saw in Keynote 522 where the carboplatin of cytamine group and first line was much more likely to have been previously treated with taxans. So what's the top line result here from that trial? So this study, the primary endpoint of the study was progression free survival, and the study met this endpoint with a significant improvement in medium PFS favoring SG versus chemotherapy, a physician's choice. Um, so with a hazard ratio of 0.62 and about a 2.8 month delta and median PFS compared to chemotherapy. So we've seen data previously from the ascent trial without a number, but the ascent 03 study, obviously first line as opposed to more refractory disease, the magnitude of benefit looks to be about the same in total months of improvement. So where would you think about using this drug? So I think very important to note is the prognosis of this patient population. And so in metastatic TNBC unfortunately, we see that there are patients who progress very quickly and even succumb to the disease in the first few months of with treatment with chemotherapy alone. So when thinking about the appropriate option in the first line setting, a trope 2 ADC, given the improvements that we're seeing with progression-free survival now consistently across studies in the first line setting, we should consider using atrope 2 ADC first. So let's talk about the other TOP 2 ADC that was explored at ESO. So this is trope on breastO2 looking at a different antibody, uh, drug conjugate Datapodumabdoxacan. How does that differ from 2 gofati can? So Datapodumabdiroxicine is another tro280C. Similarly, it carries also oppozomerase 1 inhibitor payload, chemotherapy payload. But here the antibody drug conjugate has some differences in the pharmacokinetic profile and in the dosing and a schedule of administration of the agent where data DXT is given once in a 21 day cycle, and situzumab is given on days 1 and day 8 of a 21 day cycle. And data, of course, for those keeping score at home has the same payload astratuzumab drotican, which is a very familiar drug to many. So here's the schema for tropeon breast 2 again, it's a first line triple negative study PDL1 negative population very similar fundamentally with the taxane, though I guess you could have gotten different chemotherapy options as part of the trial here. Yes, so there's some very important differences in the study design between Ascento 3. TBO2. So TBO2 did allow patients who had an early relapse from treatment in the early stage setting. They capped the DF5 up to 12 months at 20% of the overall cohort, and about 15% of patients in the overall cohort had recurred within 6 months of treatment in the curative setting. Um, another important distinction is the chemotherapy backbone. Uh, so in TBO2 patients, if they had de novo metastatic disease or had a recurrence with a DFI greater than 12 months, physicians could choose between uh nap Paclitaxel or Paclitaxel. And only for those. Patients with a DFI of less than or equal than 1 year, was there the choice of single agent carboplatin, Capocytabine or a abbilin. The other big distinction in the study design between ascento 3 and TBO2 is that in ascento 3, patients who were randomized to the control arm. We offered the option of crossing over to receive SG at the time of progression, which was provided by the study. There was no crossover option in robium breast 02 to data DXD at progression, albeit also it's important to note that data DXT does not currently have an approval in pre-treated metastatic TMBC because there are no randomized phase 3 data. So here are the first data we've seen, uh, progression free survival. again, an important endpoint. How would you characterize these data? So again, here we see that the study met one, there were two dual primary endpoints and this uh the progression free survival endpoint is met with a hazard ratio of 0.57, a delta uh in median PFS of just about 5, 5.3 months. Uh, and, uh, what we see is that these are consistent PFS benefits, consistent hazard ratio, uh, the control arm performs differently between both studies. Although if we look at, uh, historical control, for example, from Keynote 355, in fact, in a relatively similar patient population, chemotherapy and PDL1 negative disease, um, had a median PFS of 5.7 months, so very similar to the control arm here in TBO2. So, um, on this little figure I've put together a table, I guess, you know, we've talked about, uh, where ADCs are emerging and uh there's a lot of data coming forward positive disease, um, first line and beyond, uh, and now triple negative first line and beyond as well in that box of triple negative PDL1 negative, we've now seen the data for Ocento 3 ropia breast 2. Um, where are we going with all these drugs? I mean, is this the correct number to have? Is there still innovation to be had here, or is it simply time to figure out which one's the best and then just use it? That is an excellent question. So I think certainly from ESMO, we've seen consistent PFS benefit with TOP 280C. There was an increase in response rates with the TOP 280Cs versus chemotherapy. There was an Overall survival advantage to data DXD versus chemotherapy and TBO2. The Ascento 3 data for overall survival remain immature, and how crossover might impact the OS results there remains to be seen. Um, but what we're seeing are consistent benefits compared to standard chemotherapy in the first line setting for TNBC. So I think we're seeing how the TROP 280Cs are positioning themselves as the preferred therapy in the first line setting. Um, there is the question of patients who have germline BRCA1 or 2 mutations, PAB2 mutations, if in, in though in that patient population, we should be considering a PARP inhibitor instead of a rope 2 ABC, but for the vast majority of patients uh with metastatic TNBC in that first line setting, we are seeing the TOP 280Cs um as, as the, the preferred option. I do think it is important to note. What will be the next wave of therapies? There are some of these TOP 2 ABCs are being studied for early stage TMBC and if they make it into the early stage setting, then if and how shall we use them for metastatic disease. And then the role of sequencing of ABCs is there, um, uh, you know, certainly understanding the mechanisms that drive resistance to these therapies will be key to help answer that question and if and how we should be sequence, should we be sequencing antibody drug conjugates. But furthermore, Are there other agents by specific ABCs by specific antibodies that we could perhaps combine with ABCs? Uh, because in truth, there still are, uh, there are many areas of unmet need, including that early relapse group where in TBO2, we do see that improvement in PFS in the early relapse group with data DXT versus chemotherapy. Although in the overall survival subgroup analysis, there does not appear. Here to be a benefit there. And so we definitely need to develop better therapies and not just improve PFS in this poor prognostic group, but also overall survival. So there's still much more work to be done, but a very promising data from ESO for these agents. Well, exciting to see new drugs emerging and sounds like there's plenty of things to keep us busy for a couple more years. Thanks for talking about antibody drug therapy, uh, antibody drug conjugate therapy in first line triple negative. It's uh gonna be great to see what happens next. Thank you for having me.
