Harold Burstein, MD, PhD; Sara Tolaney, MD, MPH; Erica L. Mayer, MD, MPH; Nancy Lin, MD; and Ana C. Garrido-Castro, MD discuss important breast cancer research presented at the 2026 ESMO Breast Cancer Congress.
Good afternoon from Boston. It's 4 o'clock on the Friday before the Memorial Day weekend, and we're delighted you've chosen to spend some time with us talking about breast cancer breakthroughs hosted by Dana-Farber's Breast Oncology Center. I'm Hal Burstein. We're delighted you're joining us. We're gonna focus this afternoon on updates from the ESMO breast cancer meeting which was held just a couple of weeks ago in Berlin. Uh, these meetings have become important parts of the oncology calendar, and I'm delighted to be joined by a superb panel of my colleagues here at Dana-Farber. First, uh, Sarah Delaney, our division chief, who, um, uh, is one of the world's finest, uh, breast. Ecology investigators, our, uh, director of research, Erica Mayer, Nancy Lin, professor of medicine at Harvard Medical School, and leader of so many of our initiatives in our clinical research program, and Anna Garrita Castro, who is one of our faculty and uh led many of the investigations actually presented at the Berlin meeting. So, thank you all so much for being with us today. Uh, here's a biography of each of the panelists and a very handsome picture of the Dana-Farber Cancer Institute for those of you who are out of town. If you were here, you would see we're actually building a brand new cancer hospital. Uh, literally 2 weeks ago, they began the groundbreaking work and, um, we are watching it literally change day by day, and it's very exciting. So, with that, um, we'll be talking today about several important presentations from Berlin. Including a couple of studies of early HER2 positive breast cancer, the Destiny Breast 11 study, and the Fergin 02 trial, a look at hormone receptor positive metastatic and early stage breast cancer with the pre-coopera and the Capitello 291 studies. Updates on advanced triple negative breast cancer as well as early stage triple negative breast cancer, and finally, some provocative studies in the metastatic setting looking at combinations of antibody drug conjugates and targeted therapies. Finally, we've left time here for a question and answer session. We hope you'll take advantage of the chat to post questions. We have a fabulous staff of people who are working with us to moderate that, and we look forward to addressing your questions. We'll also have a sneak preview from each of our panelists on what they're most excited about at ASCO, which begins a mere, I think 8 days from now, 7 days, 7 days. We have a countdown clock in the foyer. I don't know exactly how many days and moments it is. OK. With that, let me uh bring Sarah Telaney in to discuss the Destiny Breast 11 study and an update on that trial. Sarah? Uh, thanks, Hal. Um, so at Esma Breast this year we saw an analysis that looked at residual cancer burden from the Destiny Breast 11 study. And so Hal, if you go to the next slide, um, we'll be able to see the study schema for this trial. So just to, to remind people this was a preoperative trial. That was focused on very high risk early stage HER2 positive disease. So you had to have positive nodal disease or you had to have a T3 or T4 tumor, and you were randomized to get sequential TDXD followed by THP, so 4 cycles of TDXD followed by 12 weeks of THP or to get the control arm, which was ACTHP. There actually was a third arm which was 8 cycles of TDHD monotherapy, but that arm ended up closing early, uh, due to a decision made by the DSMB. And so the primary endpoint of the trial was pathologic complete response, and we had already seen these data that were presented, uh, last year at ESMO where we saw a significant improvement in PCR rate, uh, favoring the TDXD followed by THPA compared to ACTHP reaching about a 67% PCR rate for the combination. But this analysis that was done here at ESO Brest was really trying to understand the extent of residual disease in the experimental arm compared to the control arm, so they looked at something called residual cancer burden. And so this is a scoring system that is used to really assess how much cancer is left at the time of surgery, where an RCB 0 score is equivalent to a pathologic complete response and an RCB 3 score would mean that you really didn't have treatment effect in your tumor, and so it ranges from 0 to 3. And so what they were trying to look at was how many people had an RCB 0 or RCB. One, so meaning near PCR, just not quite there, uh, because we know that these um RCB scores are very much associated with long term outcomes and so maybe if you didn't hit a PCR but you were close, those people also generally have very good long term outcomes and what you saw was that the combination of TDXD THP um yielded a higher RCB 01 score compared. To the control arm, both in the hormone receptor positive as well as the hormone receptor negative groups. And if you go to the next slide, you can see that this is also true for both node negative as well as node positive patients. So, you know, we saw in the ITT population the RC, the difference in PCR was around 11% between the two arms. And again, you're again seeing this benefit both in terms of RCB 0 and 1. And to me this suggests that we're not just driving that PCR rate home, but we're also leaving patients with a lot less cancer even if they didn't hit PCR. We kind of shifted the curve a little bit to the left, seeing more towards the PCR side and so clearly really showing benefit for this combination. And so as many of you probably recently saw, uh, we did just get an FDA approval, uh, for TDXD based on Destiny Breast 11 in the preoperative setting, but we also just saw an approval for TDXD also in the adjuvant residual disease setting and in fact these indications. even broader than the actual eligibility of the individual trials, so the indication of the DB-11 setting was actually for stage 23 disease and um for TDHD in the residual disease setting was really just for residual disease after pre-op therapy, so nice to have these choices for our patients. So, Sarah, uh, thanks for that great update. Let me just ask a couple of uh questions that the FDA approval and some of the other work poses. First, obviously, people should not be using TDXD as monotherapy here, right? I mean, the approval is in sequential combination with the THP regimen. Yeah, no, I very much agree. So that TDHD 8 cycle arm did close early because they had seen that it wasn't going to hit. Uh, sufficient efficacy to, to justify continuation, um, so yes, I would not use 8 cycles of THD monotherapy. There is some more work ongoing for TDD monotherapy and, um, lower risk disease, and so we'll learn more in the years to come. And globally, we've been using a lot of TCHP here and around the world prior to this. They didn't actually include TCHP as one of the comparator arms. What do you, what do you think is, uh, is that a, a weakness of the study, or is that just, uh, something we'll just have to figure out, uh, as we move forward? I mean, I would say certainly in the US our standard of care in the stage 23 setting is to use TCHP as you allude to, we've kind of not moved away from anthracycline given toxicity issues, but I will say I think the efficacy is pretty similar, um, you know, we have some good data from other studies that you could, you know. I think imply that anthracycline-based therapy is similar to non-anthracycline, including studies like Train 2 and the original BCRG006 study. So I think as a comparator arm, if you've beaten ACT ACTHP, I think you would have beat TCHP. I think the toxicity comparison though would have been different. So, the question we're getting mostly, and we're getting some from uh viewers right now, but we've also been getting this from colleagues around the country here is, when do you deploy TDXD? Is it upfront, uh, for neoadjuvant therapy, or do you hold your artillery, uh, in the event that they don't achieve a PA CR and then you offered a salvage treatment in the residual disease setting? What, what, what is your thinking right now about that? Uh, uh, it's a tough question, and certainly I don't know that there's a right or wrong answer, but I would say that if you have a really high-risk patient that you're meeting, I would favor using it preoperatively to start in that person with a large node positive tumor simply because, one, it gets you a really high PCR rate, right? Almost 70% PCR, and this was irrespective of hormone receptor status. But also you're only giving 4 cycles of TDHD when you use a pre-op, and we actually saw, I was actually very impressed with the toxicity in DB 11. The rate of ILD was only 4%, um, and actually half of that was driven by the THP, um, and that's very different than the 10% rate we saw in. Um, you know, the adjuvant setting where you get 14 doses, so I'd much rather give it pre-op to high risk patient, uh, but for the people who didn't get a pre-op, um, you know, obviously we at least have TDHD to think about using as rescue for them. But let's go off-piste with one more question. If you've given TDXD THP upfront and you have residual disease, are you giving TDM1 out back? Yeah, so we don't know the right answer, uh, to this question. Certainly we don't have data for what the optimal therapy would be, you know, I think the first question is, would you ever give someone TDXD if, um, obviously DBO5 shows benefit in the residual disease setting, but to me that doesn't make so much sense in a sense that. It didn't work so well, right? We had residual disease left over. I don't think giving more is probably going to be the right thing. Um, one could argue for someone who had a teeny tiny bit left over, maybe they just didn't get enough TDXT and you give them more to push them over. But if they had a lot of residual tumor, I think for most patients, I'm going to give TDM1. But if someone had a lot of residual node positive disease, I might even give them 4 cycles of AC followed by TDM1 in that setting. Excellent discussion. Let's move to a de-escalation strategy here, the Fergain trial. Nancy, can you lead us through this study? Yeah, so this is the Fergain 2 study. Remember there was a Fergain 1. So this is testing a chemotherapy-free PCR guided strategy with HP, followed by TDM-1 in the case of residual disease in patients with HER2 positive early breast cancer. So here I want to focus on the patient characteristics which are really key to understanding this study. So this study enrolled patients with only HER2 IHC 3+ disease, it didn't include 2+ disease. The tumor size requirements were between 5 and 30 millimeters, and it only enrolled no clinically node negative patients. So patients were enrolled, they had imaging, and then they received 8 cycles of HP. If they were hormone receptor positive, they also received concurrent endocrine therapy, followed by additional imaging and surgery. If at the time of surgery patients achieved a PCR, they received HP with with endocrine therapy if ER positive. If they had a near PCR, they received TDM-1. And if they had a true node positive disease, meaning N1 to N3 disease, they could receive chemotherapy of physician choice and then go on to receive TDM-1. And the primary endpoint of this study was interesting. So it looked at both greater than equal to 10% health related quality of life decline rate. Um, and the 3 year RFI, uh, next slide. So here are the baseline characteristics, and again just to point out, so 40% of patients were premenopausal. Importantly, the median tumor size was 1.8 centimeters. 60% of patients had essentially T1 tumors, and then 100% of patients, as noted before, had HER2 3+ disease. About three quarters of patients had hormone receptor positive breast cancer. Next slide. So here are the patient reported outcomes for the primary safety endpoint, and so what they saw is essentially in the orange box, so less than half of patients, 42% of patients, had a decrease in their quality of life. And so going the inverse, it says that more than half of patients experienced no significant decrease in their quality of life with this regimen. Next slide. And then if we look at the PCR rate, I think what's impressive here is that 60% of patients with this no chemotherapy strategy actually achieved a PCR. And then next, what's also very interesting is then about most of the additional patients received achieved at most had N1 microscopic residual disease. You can see that's 148 of the randomized, or not, not randomized, 148 of enrolled patients. And only 7 patients actually with this pre-op strategy with very good patient selection had N1 or higher disease at the time of surgery. Uh, Next slide. So, uh, and then uh what I didn't say is that the, the long term outcomes are not yet reported out. So Nancy, where are you thinking about using this regimen? Obviously, it's exciting to think about a non-chemotherapy regimen. Um, at the same time, our typical practice for a 1.8 centimeter clinically node negative HER2 positive cancer would be surgery up first and then Paclitaxel trastuzumab, and we know that the risk of metastatic disease is extraordinarily low. So who are you thinking about for this regimen? And before you even get to that, do you think this is a little too good to be true? I mean, 60% PCR seems awfully good. It's on par with. Yeah, I mean, I think that it's, it's, that's a really interesting question, right, because, I mean, this is predominantly also. Estrogen receptor positive HER2 positive breast cancer where we already know that the PCR rate from the uh from the blanking on it neoaffinidig the trial was or something, or yes, Neosphere was like 26%, right? And so, You know, is this just patient selection? Is, I mean, the median tumor size here is 1.8 centimeters. You know, what is really going on? Other studies have also used concurrent endocrine therapy, so we can't really propose that that is the is the reason. Um, I don't know that this is ready for prime time in the vast majority of patients. I, I do, you know, it is kind of interesting to think about for game 1 and 2 in a pair. For game one was remember the study which looked at the early PET endpoint and the patients who, you know, had a PET response went on to, to continue without chemotherapy. Interestingly, there are only about a third of patients actually had enough of a PET response to not to omit chemo. But anyways, and the long term outcomes were very good. I mean, I I think like I could imagine a study where you like if money was no object, right, you throw everything in. You put in PET, you put in cTDNA. They did the Fergain investigators did report that cycle 2 cTDNA here was was predictive of of PCR and Fergain 1. You put everything we have HER2-DX, you know, you throw it all in 3 plus IHC and And you see what you get and you really see if you can get a true PCR rate without chemotherapy. I don't know that this is ready on its own, but I do think it raises that question. Obviously, the 3-year data, which is their co-primary endpoint, will be really important to see how durable these uh also prove to be. I mean, I assume that they'll probably be very, very favorable. I think so. All right, we're going to move from HER2 positive disease over to hormone receptor positive disease and to lead our discussion here of the pre-coopera study, Erica Mayer. Thanks, Hal. So, um, pre-cooper is a really interesting window of opportunity study that's looking at oral SEDs in premenopausal patients. I think as we all know, oral SEDs have been penetrating the metastatic setting. We have exciting data in the early stage setting, but very importantly, these drugs are really exclusively used in women who are postmenopausal or. Made postmenopausal with OFS. We don't know if we can use these drugs in premenopausal patients without OFS, although certainly figuring out how we can omit OFS in certain patients would be favorable, as OFS can cause a lot of side effects and quality of life issues and lack of adherence. So preco-opera was designed to try to get at this question. So, as I said, this is a window of opportunity study that enrolled, um, premenopausal patients and offered a 28 day window exposure to one of three arms, the oral er girodrant as monotherapy, gyodetrorant with 1 month of OFS with a shot of triptoroline, or anastrozole with 1 month of triptoroline. Um, the study had, um, uh, two primary endpoints, um, that were built around, um, drops in KI-67. 1 of them was looking to see if gyridestran and tripptoroline was superior to anastrozole and triptoroline. The other primary endpoint was to see if gyridestrant monotherapy was non-inferior to gerridran with tryptoroline. So, there were 204 patients who were treated on the study. Um, let's take a look at the data. OK, so here's the primary endpoint looking at the drop in KI-67. So the first thing to see is that in all three arms of the study, all of these medications were highly anti-proliferative, so they all are highly active. However, the study did not meet the objectives as GNT was not superior to A&T. And G monotherapy was not non-inferior to G + T. So everything was active, but this was not active enough to meet the the endpoints that the study was designed to meet. Next slide. Another endpoint was looking at complete cell cycle arrest, and again there was substantial CCCA that was observed. About 20% of patients had complete cell cycle arrest, but the percentage of patients who achieved this was basically double in the groups who received the triporroline, close to 25 to 30% compared to groups, the patients who received gerridestran monotherapy, only about 13%. So we can see. Hear what the OFS, even just one month of OFS, is adding. I will also add that there are some questions about the safety of oral ser monotherapy in premenopausal patients and the impact of this on the endocrine axis. And there were actually two cases of ovarian cysts seen in the geoderan monotherapy arm. This is similar to other experiences in premenopausal patients receiving oral SED monotherapy, and we await more data from this. Study to learn about the safety issue. So, very interesting experience. Unfortunately, it's not telling us that we have an easy pathway to offer oral surges without OFS, at least when we're trying to optimize endocrine therapy with the inclusion of OFS. But perhaps there may be some patients who are lower risk for whom one might be thinking about tamoxifen monotherapy, and perhaps there's a road forgerodrant to be looked at in future trials. Thank you. Um, just to be clear, the presence of the ovarian cysts suggests that there's still residual estrogen function. Is that what the concern is? Or explain to us why that's clinically important. So back in the old days when fulvestrant was being developed, there were some experiences looking at fulvestrant in premenopausal patients, suggesting it could lead to an estrogen surge. And so there's been concern that, using oral serd without OFS could lead to, um, ovarian stimul. and high estradiol levels that could lead to either asymptomatic or symptomatic ovarian cysts. So we need to learn more about the endocrine access in the setting of oral ser monotherapy. That data will come from pre-coopera. They, they did gather it. We just don't have it as of yet. So it's the first Friday of summer. A GNT would have been nice to win here with, but it looks like it was sort of a tie, and Um, so to be clear, were one to think about this, you still need to introduce the ovarian function suppression at the same time. It would be the quick takeaway, and that probably has implications for thinking about adjuvant therapy if the oral surges make it to the adjuvant market. That's sort of the major takeaway, right? That's absolutely right. If, if Gridestran becomes approved based on the data from the Ladera trial, if that is offered to a premenopausal patient, it would need to be with OFS, and that's how it was provided in Ladera. All premenopausal patients received OFS. So let me just ask you briefly about these window of opportunity studies. Um, largely an American audience today, I think just based on the timing and, and what we're seeing of our demographics. But in Europe, they will often use sort of neoadjuvant endocrine therapy for a month or two, gauge the KI-67 response, use that physiologic response as a way to decipher whether the patient might need chemotherapy or not, and then proceed at the time of surgery. Um, I, I like the fact that this study really asked a pragmatic question about the need for the ovarian suppression. If you were, uh, uh, developing these studies, and I know you're engaged in a lot of conversations with, um, uh, companies on how to explore next-generation drugs in the ER space, what do you want most learn from these, uh, window of opportunity studies? Is it KI-67? Is it physiologic response? What, what do we really want to take away from these trials? Windows studies are a really unique opportunity because you have the ability to have tissue before exposure and tissue after exposure and have these brief moments where you can gauge a very early signal and early toxicity. So I think it's a terrific platform for emerging agents to be studied. And in particular, I think the KS 67 is a great endpoint to look at proliferation and activity, but the dual or book-ended tissue collection allows us to really look at pharmacodynamics. Is the. Drug hitting the target, is it doing it effectively? Is it safe to do it in the population? That kind of data can provide the backbone or the preliminary information that could lead into the very large adjuvant trials that that eventually lead to drug approvals. But we need to get our toe in the door in the early stage setting, and the Windows studies are a great way to take exciting targeted medicines that have emerged in the metastatic setting and begin to introduce them in the preoperative setting to really get the data to support further trials. I'm getting a question posted online here about the signal from the feline study that use of a CDK46 inhibitor in that trial, ribociclib, was apparently associated with earlier emergence of mutations. I don't actually remember that. Does anybody remember that particular study? All right, well, then, uh, I'm not seeing a wave of hands here, so I'll ask our participants who are online to help us by posting that link and we'll get some more information. So, let's continue on with the discussion of ER positive disease, but shift to the metastatic setting and talk about an update of the Capitello 291 study, uh, looking at captive assertive in uh PC PICC3CA pathway mutated tumors in combination with Fulvestrant, and Sarah's going to lead us again here. Oh, thanks, Hal. So, um, the Capitella 291 study was a trial that looked at adding cappiviertin, the oral AKT inhibitor, to fulvestrant. The trial had an analysis both in an ITT population as well as in a PI3K pathway altered population. So if you go to the next slide. You can see that the primary endpoint for the trial was progression-free survival, where it was assessed both in the pathway altered and overall population. We've already seen those data where we did see that the majority of the benefit for PFS was really being driven by that biomarker enriched population. That's what did lead to the FDA approval of captive assertive within the PA3KP10 AKT altered group. Um, but what we saw at ESO Brest was data for the secondary endpoint, which was overall survival and also saw data for PFS2. 1 caveat that I would note is that the overall survival endpoint was not well powered, so it only had a little over 50% power to assess overall survival. So I will say that I think we have to view this with a bit of caution. Um, but when you look at the overall survival data in the overall, um, population, you can see the curves are in large part overlapping. Uh, this was not formally tested in the ITT population, but if you go to the next slide. You can see within the PI3K altered population, you do see a trend favoring benefit in this group with a hazard ratio of about 0.7. They also did a really interesting exploratory analysis where they looked at outcomes in the PI3K altered population in the post-CDK setting where they saw about a seven month delta in terms of OS within that exploratory subgroup. And so I think while we can say that there is not a statistically significant OS benefit, certainly in the group of patients that we're using the drug in the PI3K altered population post CDK, there does seem to be a trend. And this is in the setting of some imbalances in subsequent therapies where we did see there was more use of targeted agents within the control arm, where there were more patients, for example, who got PA3K pathway altered drugs subsequently, including drugs like Evolimus. There was some alalis sub utilization post, but again some imbalances which obviously can have some impact on OS. Find OS is very challenging endpoint, particularly in global trials where there are differences in drug access across many different regions, and here again, a very underpowered analysis. So my takeaway is I think cafesert remains a standard of care option for patients who have a PA3K altered tumor based on the PFS benefits and certainly a trend in OS in the biomarker-driven population. So, let's talk about endpoints a little bit cause you just raised some really interesting questions about what we should be looking at with these longer-term follow-ups in, in global studies, and I'll invite the, the whole panel here to weigh in. I, I think I put a typo in the slide. It's not OFS, it's OS and PFS too. Um, but, you know, in ER positive breast cancer, It is the case that the vast majority of patients now have opportunities for multiple lines of endocrine therapy. We then have 3 commercially available ADCs in the United States. We have, um, a dozen chemotherapy products, uh, that we, in theory can introduce. So, um, while we tend to focus on OFF on uh PFS for registration, Um, are we, are we selling it a little, are we making it a little too easy to say that we shouldn't be looking for survival benefit? Because that, if ultimately, you know, the next line of therapy isn't changing the natural history, the long-term natural history, what should we be measuring, as the endpoint for its use? I think you bring up a really challenging question. I think in a disease that has such a long natural history, overall survival is very challenging to assess, right? It is the ultimate end point. Obviously the goal of everything we do is to allow patients to live longer and to live better, and it should be what we are looking to achieve. I think the challenge is, are we actually proving it for the drug that we're studying when someone may be able to receive several subsequent lines of therapy and if they're received in an imbalanced way, how are we actually assessing the impact of the drug that we're actually studying, right? And that's what I find tricky. Um, and so yes, I think OS is, is what I'd love to see, but I just don't know that I feel 100% confident in it again when there are so many subsequent lines of treatment. You know, I think if you have a disease where the survival is short and you don't have a lot of subsequent lines of therapy, that is a different issue. One could say, could you look at PFS 2, which is really looking at the time of randomization to time of progression on the next subsequent line of therapy, saying that maybe, you know, you're allowing someone to do better even with, you know, progression on the next line. I think the challenge there is also did you allow crossover or not, right, because if I'm studying, let's say we're studying capive assertive here, um, you know, then you'd need the control arm to cross over to get some type of PA3K pathway inhibitor, right, to make sure that there's a balance when you're looking at PFS2. But in truth, not very many trials. Have built in crossover where it's provided and you know in truth that is risky for a drug company right because that's obviously going to impact your OS endpoint and then if regulators are looking at you achieving OS that is also very challenging and so I do think this needs to be sorted out a bit and I think with our regulators we need to better understand. You know what they're willing to look at as we're doing better and better and as people are living longer and longer and we have so many drugs that can impact OS's subsequent lines of treatment where they're not equally accessible, I think this is becoming more challenging. I would agree, and you know, you introduced the idea of these global studies and I think there are two real questions there. One is, who are the patients going on to these studies, because in the US, Western Europe, Australia, New Zealand, the majority of patients with ER positive disease will have been diagnosed previously, will have had adjuvant therapy, endocrine therapy with or without chemo. So when they recur, if they do recur, you know, first line treatment looks a lot different from someone who walks in with de novo disease. The back half of this is that particularly in the United States, there is a huge amount of um medical intervention for appropriate palliation, radio palliative radiotherapy, paracentesis, thoracentesis, other supportive care, adequacy of pain control, all of these things that play into survival, willingness to consider more therapy, and And patient quality of life, and I'm just not always convinced that around the world those same standards are met. And so you have to again wonder about the meaningfulness of overall survival based on geography. Nancy, did you want to weigh in here? Yeah, I mean, I think the heterogeneity is a really big issue for diseases with a long time horizon, so. You know, you have ER positive disease, easily people might receive 8 lines of therapy. You can control this next line of therapy in a trial. You could design a trial where you have forced crossover, not forced, but you have, you know, implemented crossover for the second line, but you're not going to be able to design a trial where you constrain 3rd, 4th, 5th, 6th, 7th, 8th line of therapy. And you're not going to, as you say, be able to constrain the supportive care that comes around it. So I just think that it's very hard. And then it becomes more of a global question, not global internationally, but a question of what is the absolute PFS delta and what is the quality of life delta, and how do we consider those as far as how beneficial a treatment is in that first line setting. Otherwise, I think. OS for HR positive is very, very hard because of the issues of heterogeneity in the later lines. Erica. Yeah, I'm, I'm thinking about the first line CDK46 inhibitor studies and, you know, how for many years we considered the drugs are the same, the PFS is, you know, the benefits are the same, and then we saw OS data with, you know, differential results, whether those actually reflect true differentiation among the agents or whether it reflects where the trials were done, how the data was collected, what happened to missing data, how the trial was structured. Empowered for a secondary endpoint like overall survival, you know, those sort of trial-specific issues might play into what the end result is. Regardless, it does change what we do and practice changed when that data came out. So, you know, it's, it's so important and yet it's so challenging. Well said. All right. Well, we've talked about HER2 positive and ER positive, and we've saved triple negative here for uh Doctor Garria Castro. Anna, lead us through a couple of interesting studies. Thanks so much, Hal. So at ESO Breast, we saw the results of the MirinA trial looking at the addition of an immune checkpoint inhibitor to capoccitabine in the adjuvant setting for patients with residual disease after preoperative chemotherapy. And we know that currently we have several options for these patients who have residual disease after new adjuvant treatment, uh, for early stage TNBC, capecitabine based on the results from Create-X, Olarib for those patients with germline BRCA mutations based on the Olympia study, both of those trials, um, enrolling patients after neoadjuvant chemotherapy prior to approval of pembrolizumab for early stage disease. And now, uh, the immune checkpoint inhibitor pembrolizumab that is continued in the adjuvant setting for those patients who receive neoadjuvant chemo plus immunotherapy. So this trial, Marin um is looking specifically at whether adding the immune checkpoint inhibitor, etezallizumab, which is a PDL1 inhibitor, to capecitabine, uh, could improve long-term outcomes with the primary endpoint here being invasive disease-free survival. So patients with a triple negative breast cancer who had at least 1 centimeter of residual disease in the breast and or positive lymph nodes who had received neoadjuvant chemotherapy, not. Uh, with immune checkpoint inhibition in this trial, uh, were randomized to capecitabine, and this was at a slightly lower dose than the control arm, 2000 mg per square meter for eight cycles, um, in combination with otezallizumab, uh, to complete a total of 1 year of the immune checkpoint inhibitor, or, uh, to receive capocitabine alone, and this was at a higher dose of 2500 mg per square meter, uh, for 8 cycles. And so, um, if we go to the next slide here, the invasive disease-free survival primary endpoint was not met in the overall patient population. While the curves do appear to slightly separate over time, um, with about a 4% delta in uh invasive disease-free survival at 3 years, uh, that is maintained at 5 years. This did not reach statistical significance with the hazard ratio of 0.84. The median follow-up here was just over 4 years, and if we go to the next slide, what was interesting to see was a signal that perhaps in patients with PDL1 positive tumors, and this was defined um by a positive uh staining using the SP-142 assay in either tumor or immune cells, that in this PDL1. Positive subgroup. There appeared to be a trend favoring the combination of capocitabine plus otezalizumab, but this is a subgroup analysis from the overall trial, and this did not reach statistical significance, so should be interpreted with caution. As you can see on the right in the PDL1 negative subgroup, uh, the Kaplan-Meier curves, um, uh, do overlap. So, um, I take it from the tone of your comments, you don't think this is immediately actionable here. So, I don't think this is practice changing, and it's aligned also with some of the uh previous um data that we've seen, for example, from the A Brave study looking at vellumab in the adjuvant setting, um, post neoadjuvant chemotherapy without immune checkpoint inhibition, where there wasn't a significant improvement in IDFS uh with the uh adjuvant vellumab in that trial. And it does pose the question that you're, that you're, uh. Raising here of what is the role of immune checkpoint inhibition in the adjuvant setting if it has not been received in the early-stage setting. Similarly, we also saw an impassion 030 that use of adjuvant otezlalizumab, um, uh, in, in patients, um, after resection of their primary tumor did not improve long-term outcomes. So I do think it, it does pose that question of how important is it to have the tumor in situ to elicit that initial anti-tumor. Immune response really to derive the most benefit from these immune checkpoint inhibitors. The signal in this trial in MRA of perhaps improved outcomes, a signal for improved efficacy for those patients with PDL1 positive tumors is intriguing, but I think that requires further validation. There are several ongoing phase 3 trials that are looking now at combinations of trope 2 antibody drug conjugates with immune checkpoint inhibitors. Um, in the adjuvant setting, um, and it'll be interesting to tease out what are the contributions, uh, potential contributions of ADC's immune checkpoint inhibitor versus standard, uh, immunotherapy, um, alone in those patients. Well, we began our highlights with ADCs, and I think we're going to end them with ADCs also because we are living in an ADC era. So why don't you continue on and we'll talk about a couple of provocative studies here, uh, that you were. Involved with, obviously, um, tell us about Sassy IO and Saine. Thanks so much. So, uh, a couple of investigator-initiated trials led here by, uh, Dana-Farber investigators. So SassOHR positive, uh, was a randomized phase 2 study that, um, enrolled patients with metastatic hormone receptor positive HER2 negative breast cancer who had received prior endocrine therapy and 0 to 1 prior lines of chemotherapy in the advanced setting. And randomized patients to the trope 2 antibody drug conjugate sacatituzumab govitecan. Uh, with pembrolizumab versus, uh, sassatuzumab gobetecan alone, and the hypothesis of this trial is that the toposomerase one inhibitor payload of this antibody drug conjugate could perhaps synergize with immune checkpoint inhibition even in more immune cold settings such as HR positive uh disease because of some of the immunomodulatory effects that the that DNA damage can induce in the tumor microenvironment. Uh, initial results from this study, the primary results were presented at ASCO 2024. The primary endpoint of the trial was progression-free survival in the overall patient population, and that was not met. There was no statistically significant difference, uh, between, uh, the treatment arms, uh, in the overall population. However, there was a signal that in patients with PDL1 positive tumors, um, uh, there was a numeric. trend favoring SG plus pembrolizumab um versus SG alone for both PFS and OS. And so at ESO reast here, the final results for overall survival were presented and very consistent with that initial analysis. There was no statistically significant difference between treatment arms in the overall patient population and in the about 40% of patients who had PDL1 positive tumors. There continued to be now with additional um uh follow-up, now more than 3 years of median follow-up, a trend favoring SG+ pembrolizumab for um those 40% of patients with PDL1 positive tumors, both for PFS and OS, um, uh, though that is not statistically significant and a subgroup analysis that should be taken with a, um, should be, um, interpreted with caution. Again, so, you know, what's interesting is we keep seeing this, if you select these hormone receptor positive tumors for a little bit of PDL1, maybe there's more signal of activity, studies are under power, differences are more subtle, it, it's hard to get a clean takeaway. Why don't you continue on with the satine trial? And so, uh, Sain was another phase two investigator initiated trial led here by my colleagues, Dr. Tarantino and Wax, um, looking in the HER2 positive metastatic setting at the combination of saccetuzumab govetecan with trastuzumab. In a more pre-treated setting in patients who had received prior taxane trestuzumab and trestuzumabdoxigin in any setting for HER2 positive disease. And so this was a single arm phase 2 study with a Simon two-stage design with the primary endpoint being objective response rate. And um if we go to the next slide, we can see that um that uh Simon too, that first stage did not meet um its uh primary endpoint and so stopped after, um, after the, the 1st 27 patients were enrolled, and here you can see that there was only one confirmed response, uh, in all of these, uh, in these patients. I think what's very important to note is that all of these patients had received prior, uh, trastuzumab Daruxigin. And so, um, it'll be important to understand, um, if there were mechanisms of resistance that developed directly to the payload that may have conferred that, um, intrinsic resistance to satusumab govitecan here in the, in the trial. And so correlative analyses from this study are ongoing. Let me just, before we get to the general conversation, let me ask you a quick follow-up here, which is, there were a couple of reports at ESO Breast and formal studies as opposed to chart reviews and as opposed to um larger sort of data set analysis, where they looked at ADC after ADC with very similar drugs in the sense that they all had exotecan or irinotecan derived payloads. And the marginal benefits look really small. Yet, when I see patients in consultation in my own practice, a lot of patients are getting one ADC after another. How much do we really know about the value of that strategy? It's an excellent question. Um, there are several retrospective studies, um, with the caveats that, that, um, those limitations that these, that these studies have, um, in terms of heterogeneity and, um, in prior lines of therapy, hormone receptor status, but that have looked at the activity of sequential saccetuzumab gobetecan primarily in trastuzumabdoxigin, um, or vice versa, both. HR positive and triple negative metastatic disease. And I think the take-home message from these, uh, retrospective studies is that the time to progression on that second ADC is usually shorter than the median time to progression from the first ADC. But what is interesting to note in these retrospective studies is that there are some patients who do appear to have, um, the same, if not longer time to progression on the second ADC than the first. And so Understanding who those patients are and what is, um, the mechanism that drove resistance to the initial antibody drug conjugate, I think will be key in trying to understand what is the role of sequencing of ABCs and is it primarily the payload? Is it perhaps the target? Can you change the payload or can you change the target to overcome that mechanism of resistance? And there are several prospective trials that are ongoing to try to address that question. That's great. It's gonna get worse because I believe about 4 hours ago, the United States FDA approved uh Datapotumab droxican for triple negative disease. So, the permutations and the pathways get, get more complicated. And do you switch the payload? Do you switch the targeted antibody? Do you switch both, um, more to come. But, um, it's a complicated space right now, uh, breast cancer. So, um, these data that we've been discussing were from all of 2 weeks ago, but ASCO is right around the corner. So, um, uh, we cannot go more than 1 month without an update on major studies in breast cancer. Uh, we're all looking forward to going to Chicago. Uh, highlights will include the line at the Starbucks on the main floor of the convention center, and more seriously, the chance to really dive into the meeting and to see colleagues from all over the world and to take advantage of the post. sessions, it, it's, uh, always an extraordinary meeting. I've asked our panelists to skim the, uh, material that has been put forward so far for the program for ASCO and to come up with some ideas for things they're particularly excited about or looking forward to. Um, and as we do that, I will invite our audience again to post questions or comments in the chat, which I'm monitoring, uh, at the same time. So with that, maybe we could go to our panel and say, Nancy, what are you most looking forward to at ASCO besides the Starbucks and that kind of thing? I think that the Optima trial will be very interesting. So this is this is a study of almost 4500 patients with hormone receptor positive HER2 negative early breast cancer who got Either standard chemotherapy, endocrine therapy, or they had PAM50 directed treatment. So based on their ROR score they either did or did not receive chemo. And the thing I think that's very interesting about this study is it included N2 patients. So that's those are patients not included in our responder and also Included premenopausal patients that actually mostly received ovarian suppression, which of course is a big confounder and problem with all of the previous studies where you're not sure if the chemo effect that is being seen is because of ovarian suppression effects of chemotherapy. So I think that will be very interesting. And of note in the Optimma study, in the younger women, the premenopausal women, they insisted upon ovarian function suppression. So we've all been, and that study also has this Optima Young expansion. So, I don't think we're going to see that in this presentation, but there's an expansion to include an additional several 1000. So I think it's going to be over 3000 premenopausal patients at the end of the day when Optima Young's included. One of the big persistent questions has been even in the study of a low genomic risk score, be it MammaPri or oncotype DX, that, you know, how much of that benefit might be from simply ovarian suppression. So we're going to see both ends of the spectrum, right, premenopausal and to disease, and I think those are really important populations that we don't have as much information as we'd like so far. So that is abstract 500, which is always means that's the number one abstract for the early and local regional breast cancer sessions. Uh, let me go to Erica Mayer. What's, what are you most looking forward to? Um, well, I, I love trying to figure out the world of oral SEDS, and, you know, a few months ago or weeks ago, we saw a press release from the Persevera trial. This is one of the two first line trials looking at an endocrine sensitive population, um, randomizing patients to receive. Oral cED in the case of this trial, Grid Erant with CDK 46 inhibitor versus Standard of Care AI and CDK46 inhibitor, and we had a press release that the trial did not meet its primary objectives. We will hear more Tuesday, like noon, like the last minute of ASCO. We're going to get this data. Um, but I, I think it's really important because, you know, we, we have so many nice signals of activity with oral SERDS in, uh, patients whose cancers have developed an ESR-1 mutation, um, that's led to the approval of several of the oral SEDS as monotherapy. And we also have had the positive data from Ladera in the early-stage setting, um, which was, uh, using monotherapy without CDK46 inhibitor. Um, and we would anticipate in the early-stage setting, not many patients have an ESR-1 mutation. And so, Persever is going to hopefully help continue to help us learn what is the active, what is the activity of uh an oral CERD in a population who probably doesn't have much in the way of ESR1 mutation. And also, when we combine it with a CDK46 inhibitor, we're still getting the benefits from oral CERD or that all swamped out by the benefit from the CDK46 inhibitor. So, I, I'm really looking forward to seeing that data to help try to put this puzzle together. And I'll note there is another trial, Serena 4, which is very similar design, very similar setting, and we're waiting on that data. So that will hopefully eventually complement what we see from Persevera. It's a really good point that I think people will look at the data for Perseverra, which is obviously a first line metastatic trial, but immediately begin to think about the adjuvant setting and that question of whether in high risk patients, you know, you need one new targeted approach, whether it's the oral cERD or both with the CDK 46 or CDK 46 with our traditional drugs. So that looms as a very important question. Um, we'll go next to Sarah, and Sarah, before you do, we have an interesting question, um, that since you discussed the HER2 positive space, what about PICC3CA testing in HER2 positive disease, and does that affect the way you think about some of the neoadjuvant choices with, say, chemotherapy and the antibodies versus ADC-based therapy? So we know that about 30% of HER2 positive breast cancer cases are PI3K mutant, and we also know that at least in the metastatic setting in general, PFS is shorter with HER2 directed therapy in the PI3K mutated tumors compared to a wild type. Um, so the question is being asked is, should we be testing to know if someone has a mutation or not? You know, I will say I do personally test. I, I will say I think it is controversial though, you know, right now, I think our big conundrum in the first line metastatic HER2 positive setting is who should get TDHD plus pertuzumab, who should get standard THP maybe as induction followed by a maintenance strategy. And we do actually have data that in the PI3K mutated tumors, the PFS with THP generally is substantially shorter for a mutant compared to wild type, but actually when you look at the TDXDP pertuzumab data, you actually see outstanding outcomes that are not dissimilar and mutated in wild type. And so it does make me favor for a PA3K mutated tumor, a THC pertuzumab approach, uh, because again, the PFS is just so much more robust, and again, you're not seeing that detriment like you see with THP based therapy. Um, so you know if you were in this conundrum, it might influence you when making that type of decision and in the future we may actually have PI3K mute mute uh specific inhibitors in this setting. The AAA 122 study is just completing enrollment, and that looked at adding abilliib as a maintenance strategy after an induction period with HP. So, you know, in the future again this may become more standard now, not totally standard, but could be considered. Great. So, and Sarah, let me just expand on that for one second, which is in, in the current maintenance setting, would you let that affect your choice of switching to antibodies alone versus continuing, say, TDXD in the first line setting? So if I had someone on TDXD plus pertuzumab, and I'd already made that decision, I don't think the mutation would necessarily make an impact. I don't think we know enough truthfully because we don't know what happens to someone who gets TDXDP and then goes on to a maintenance compared to someone who doesn't. And so we'll have to understand that more with more studies that are coming and ongoing. All right, so fair enough. Uh, and what are you looking forward to in Chicago? Well, we heard about, um, a couple of really exciting studies of Optima and Perseverra. I think, uh, another exciting study is the Victoria One trial. We've seen the data from the PI3K wild type portion of the trial which we saw, uh, at ESO looking at the use of getatolisi in the post-CDK 46 inhibitor setting. Um, and now we will see data for this agent in PI3K mutated tumors. So this study looked at uh fulvesterran getatoliib plus minus palbocicli compared to fulvesterran alpelisi, and we've already seen the press release, uh, suggesting positivity with the primary um efficacy analysis, including the triplet compared to Fulvester and alpelissi, and also benefit in the secondary endpoint for doublet of fulvesterrant getta versus Fulvester and alelissi. Um, so I think it'll be interesting to see how robust that is because in truth right now we use Fulvestrant cappiviertib for our patients who have a PI3K mutation, and we know at least in the Capitello subset data post CDK that only got us about a 5.5 month PFS. So we are really looking to see if we could do better here. Um, obviously, you know, the, the challenge with Gatulsi is it is an IV drug given 3 out of 4 weeks, but on the flip side, if you really. Hit a home run with PFS in a setting where we don't do so well, this would become really an attractive strategy. The first iteration of the Victoria trial was sort of surprising to me because it was focused on the wild type, and the large literature to date had not suggested major differences. What do you think accounts for that? Have we just not had potent enough inhibitors of PICC3CA? Is there something structurally different about getatoliib that makes it different, or have we somehow just missed a signal because of inadequate numbers or study design features or things like that? This agent is different, so it actually does hit MTOR, so it's an mTOR and PI3K inhibitor. So I think the benefits that we're seeing in the wild type population are because of its robust mTOR inhibition, where we know mTOR inhibition works irrespective. PI3K mutation status, whereas in the PI3K mutant population, I'm hoping we see an even larger benefit because of its ability to also hit specifically the PI3K pathway. And so I think we're all anticipating a much larger PFS benefit. Ana, I've left you the hardest task. Everyone has picked off the low lying fruit here. What are you looking forward to at ASCO? I suspected Sarah, Nancy, and Erica might have commented, would comment on these trials. Um, they're certainly exciting data to look forward to at, at, at ASCO, um, but staying in line with the antibody drug conjugates, I'll say, um, very eager to see the results of the first, uh, randomized phase 3 data, uh, that will report out for a bi-specific ADC and triple negative breast cancer. So, Um, the, uh, bi-specific antibody drug conjugate, um, Isobriin, which targets, um, HER3 and EGFR. With a toposomerase one inhibitor payload compared to standard chemotherapy of physician's choice in the first-line metastatic TNBC setting for patients who are not candidates for immune checkpoint inhibitor, um, had a press release, um, already, uh, stating that the dual primary endpoints for PFS and OS were met. And so, we will see these, these data presented at ASCO, um, and, uh, certainly eager, eager, eager to see the results. We now We have, as you noted, uh, the approval earlier today for DadoDXD as a trope 2 directed ADC in the first-line setting for this patient population. We also saw the data for sascetuzumab gobitecan from Ocento 3, similarly for those patients who are not candiermine checkpoint inhibitors, um, in, in that first-line setting. And so now, we will see, uh, the first data for a bi-specific ABC in this, in, in this same setting. Agreed. And these bio-specifics are really interesting, uh, you know, the ones that are either PDL1 and VAF or in this case, HER3 in VAF, and I, I, I think there's, uh, there, there's gonna be a lot there. I, uh, you know, it's gonna be a lot of brute force empiricism to figure out which ones look best and which of the bi parts of the bis specific you want to go with, but, um, they're a very exciting class of drugs and, and ones that You know, really, I don't think anybody was talking about 8 or 10 years ago, you know, it's, it's, it's new and um Gonna be great to see. Uh, for those who are there, I would certainly encourage you to drop by the plenary session where two Dana-Farber faculty members will be giving, uh, uh, two of the five plenary discussions. We're very proud of our group. Um, Mary Ellen Teplin will be discussing prostate cancer treatment and, um, Brian Wolin, uh, discussing what is probably the molecule of the month, uh, the new RAST targeted drug for advanced pancreatic cancer. Uh, and, uh, if you want to find any of us, my guess is we'll be in the front row of the plenary session, that's hall B1 on Sunday afternoon. I wanna thank Nancy, Sarah, Anna, and Erica for a fabulous discussion. We hope you've enjoyed it. We are doing more of these, distributing. The online. Uh, you can find us at our Dana-Farberry YouTube web page. You can find us on Twitter. If you'd like to have specific programs discussed, please reach out to us. And, uh, between now and then, we hope we see you in Chicago and down the road. Thanks, everybody. Have a great holiday weekend.
