ESMO Breast 2026 Highlights - VERITAC-2, PREcoopERA, PHERGain, SATEEN/BRE-354, TROPION-Breast02

Hello and welcome back to the oncology brothers podcast. I'm Rahul Gossane, here as always with my brother and co-host, Rohit Gossane. Esmo breast 2026 in Berlin just ended, and we're also days away from Asco 2026. There is a lot happening throughout the year and our hope is that these bite-sized discussions are keeping you afloat. Today we're focusing on some key studies from Esmo 2026 and few approvals that we've seen over the last few days. And for this, we're excited to welcome back Dr. Erica Hamilton from Sarah Kennan Cancer Research Institute. Erica, you're probably just getting over your jet lag but we appreciate you joining us. Yeah, happy to be here. Erica, welcome back. There's a lot happening in breast cancer space. That is before Esmo excitement around ODAC FDA meeting on chemisestorant. And recently, approval of Vepi-gestorant, a new class of drug got approved for ESR-1 mutated breast cancer. And just again recently, for her two positive space, what we've seen is TDXD in Neoagement and Adjuvant settings. Well, coming back to Vepi-gestorant, which is with Vertex2 study, Erica, you led this effort. Can you please briefly touch on the study design, mechanism of action, and findings from Vertex2? Yeah, absolutely. I think you've already highlighted. We've had two FDA approvals within 15 days in May for breast cancer. So very, very exciting right here in between Esmo Breaston and ASCO. So Vertex2 was a registration trial of a pro-tac. And some people kind of want to group this in with the oral serons, but really it is a unique mechanism of action. So this is a proteolysis targeting chimera. And it really harnesses the ubiquitin proteasome system, which is kind of the intracellular trash or disposal a mechanism where this compound kind of binds the estrogen receptor flags it for ubiquitination, which essentially signals to the cell that this is trash or waste, then the estrogen receptor gets degraded. Then this molecule can actually be recycled and used again on another estrogen receptor. So it has iterative activity. That's different from an oral serr. So it really is a unique mechanism of action, but you can think of it as a degrader. And so this was a very straightforward clinical trial. Everyone had already seen indricran therapy in a CDK46 inhibitor. So a very uniform population, patients were allowed up to one additional line of indricran therapy, no prior assert or prior chemotherapy, and patients were randomized to either receive full vestrant or VEPDegastrant, which was 200 milligrams orally one stale. As we've seen with a lot of these oral indricran agents, the benefit was restricted to those patients that had ESR1 mutations. Progression free survival was five months with VEPDegastrant and was 2.1 months with full vestrant. And so again, this received FDA approval on May the 1st. So this joins in lieu nesterent as well as in lieu nesterent as an option for our patients that have ESR1 mutations in the second line setting. How this compares, this was similar to LSestrant in that trial population. Everyone had seen a CDK46 inhibitor in terms of in lieu nesterent. Remember in that trial, you'll see PFSs that are a little bit longer, but in that trial, not everyone had seen a CDK46. So that's really why you see longer PFSs there. - Erica, thanks for touching on that. Based on these findings, we now have three oral agents for ESR1 mutation out in clinical settings, keeping the side effects in mind, including the QTC prolongation. How are you going to pick one over the other? - Yeah, absolutely. So the QT prolongation really isn't clinically significant to me in the practice. Our QT prolongation was about 11 milliseconds, so really not significant. It's recommended to do a baseline EKG, but you do not have to monitor it while patients are on therapy. We saw the most common side effect being nausea, and that wasn't about a quarter of patients, a quarter any grade fatigue. So said a different way, about three quarters of patients having no fatigue at all, nausea on the other hand, only in 13% of patients. Again, this was all kind of low grade nausea. What you didn't even see on the adverse event table was diarrhea because it didn't even meet the 10% threshold, only 6% low grade diarrhea. So this really was a quite clean drug. We saw only 3% discontinuations, only 2% dose reductions, really telling us that the vast majority of patients were able to tolerate this drug. So I really think that that's encouraging. - Thanks for summarizing that, Erica. What you stated with WebGiDestrant, QTC is certainly a concern, but we are seeing low prevalence there. With LSS, you have to worry about nausea and vomiting along with that dyslippidemia. As a result, checking for lipids is extremely important with that. With immunosteorant, one has to worry about diarrhea, which is not too much of a concern with WebGiDestrant. Now moving along into other ESR1 mutated drugs, what we saw was at SABCS 2025, Geardestrant. This was based off of LDRA study in early disease itself, but we are still waiting a approval here. What we saw here at SABCS 2025, focusing on Geardestrant, the study was pre-coup error trial, looking at the importance of ovarian function suppression in pre-menopausal, in early stage breast cancer, whether ovarian function suppression is adding any benefit with endocrine therapy or along with Geardestrant. Erica, what can we walk away from this study? - Yeah, so this was essentially a window of opportunity trial, so looking at a small duration in the neoagevent setting where tumors are still intact in the body, and we really saw kind of three different arms, Geardestrant, the oral serdalone, Geardestrant with ovarian suppression with triptorellin, or a nast resolve with the triptorellin. And we saw really not statistically significant differences between these arms, but we did see that the Geardestrant with the triptorellin had the greatest anti-proliferative effect measured by K67, and the reduction there was about 79.6%, so about 80%. It was about 74% with a nast resolve in triptorellin, and it was about 68% with Geardestrant alone. So takeaways, Geardestrant alone certainly reduced the K67, so we didn't need the ovarian suppression, but certainly our greatest benefit came from when we used the Geardestrant with the triptorellin, again, in this population of patients that were pre-minipausal. And I think this was a big question for us, really with the class of oral serds, a lot of our patients, our pre-minipausal, do we need the ovarian suppression? It didn't meet a kind of non-affery already, but I think did reassure us probably with the metastatic setting that we are giving our patients benefit by giving ovarian suppression in that setting, or at least that's what I took away from it. And again, I just want to echo that the big key takeaway here is if when oral serds become available in early settings, this is not going to negate the importance of ovarian suppression. All right, now on to her two positive disease. For T2 or any node positive disease, TCHB in new adjuvant settings had been the standard of care. Just a few days ago, we also saw TDXD get approved in neo-adjuvant settings based off destiny breast 11 for T3 or node positive disease. But we've also seen data for a new carpe, where at THP and using that MRI to guide what next was non-inferior to TCHB granted, we still need longer, more mature data for these de-escalation trials. Here at ESMO, we suffer a gain trial looking at that additional de-escalation strategy. Erica, what did this study show? And importantly, today in your clinic, who are you considering de-escalation strategies for, and who will get TDXD or TCHB? Yeah, I think this is a difficult question. We certainly have de-escalations like the APT regimen. We use it for smaller tumors. We use it for patients that are older. This is not the first time we've seen the fur gain data. But what we really saw in this disclosure was the five-year invasive disease free survival rate for patients that did well on this regimen. And it's kind of a tough schematic to follow. But essentially, patients, they had to up to two cycles of HP alone with or without endocrine therapy. And if they did well on this by imaging, which was a pet, they could continue for six more cycles. If they had a PCR to essentially now eight cycles of HP alone with or without endocrine therapy, they could continue their HP with endocrine therapy. If they didn't have a PCR, then they switched to getting TCHBs, who kind of standard chemotherapy. So essentially, if any point during this algorithm, they weren't a responder, they could switch into getting chemotherapy. But what our disclosure was here at the meeting at AsmoBrest, of those patients that had a PCR and never got chemotherapy, they remained on the HP with or without their endocrine therapy. What was their five-year invasive disease free survival? And it was 92.4%. So giving us that confidence in long-term data that these patients did very well over time. And in fact, I think this is really encouraging data to show that giving a patient an opportunity for their own biology, kind of with their tumor to dictate care is really an encouraging strategy. I think a lot of patients are wanting this. I mean, there are some limitations. Obviously, this requires imaging. This is a very dynamic process. This is a kind of one-size-fits-all, kind of like an APT regimen, where you're looking up front size, et cetera. But I think this is where we're headed, really kind of this dynamic risk assessment where you're letting patients own biology care. At the end of the day, the idea of de-escalation is not to compromise that efficacy in having that favorable side effect profile. Erica, based on this, at least from the clinical takeaway, who's that right patient that you would rather consider this approach? Certainly, our patients with smaller tumors, I would feel very comfortable doing this. I also think our patients that are older or have comorbidities, where you're really worried about their tolerability with chemotherapy. I would consider this, and patients that are really just motivated to wanting to do this. You know, I don't think you're going to lose very much with two cycles of good-targeted her-to-directed therapy. - That's good. - And again, before we run away from this topic of de-escalation or escalation with TDXD, Erica, with the recent approval of DB11 for that T3, is it going to be TDXD for you or TCHP? Who's going to get TDXD versus TCHP in ureclinic? - I think this is a little bit of a controversial question right now. I have pulled a lot of people, I've heard a lot of people talk. I think most people are favoring a little bit, the DBO5 compared to DB11 right now. I'll have to say that I'm in the DB11 camp. I think for patients that are really high risk up front, I'm actually favoring DB11. I really believe in the prognostic impact of having that PCR. I like being able to give something on the back end. I really like that four cycles of TDXD, not having to monitor as much for ILD, only having to give the four cycles. I think DBO5 is a very attractive strategy as well. I do think that we're going to end up with some more trials in that DBO5 space where we might be able to escalate beyond TDM1 there. I think the moral of both DB11 and DBO5 is that trust who's a Mab Drucks to camp is here to stay in early HER2 positive breast cancer. - And just quickly for the completion, say I just want to make sure that DBO5 was where you have aggressive, residual disease. Instead of TDM1, patients got TDXD and there was a significant benefit, which also got to prove based on this study. - Right, I'm gonna say that four cycles is definitely more appetizing, especially when you tie in the side effect profile. All right, moving along into HER2 positive space further. What we saw here at ESMO26 was SOTIN trial. That is use of trust to Mab and SESIT to Mab after disease has progressed on TDXD. And this was rather an important study because we are often wondering how to utilize 180C after another 80C utilization. Erica, in conjunction to this, you all to present it, B-R-E-3-5-4, focusing on HER3DXD. Can you touch on these two studies and what can we exactly learn from this? - Yeah, so both of these ask the question of TOPO1-80C after TOPO1-80C. So Dr. Tarantino presented this SACTEEN trial and this looked at SACITUZAMab GABA TECAN in a spot that you haven't seen it in HER2 positive breast cancer. So again, looking at SACTEEN with a TESTUZAMab. And this again was in HER2 positive breast cancer after patients had already seen TESTUZAMab GABA TECAN. It didn't have to be immediately after TESTUZAMab GABA TECAN, but everyone had already seen that. And the way this was set up, it was an initial 27 patients. If there were three responses, then they were gonna go on to enroll more patients. If there weren't, that was futility. And so what you can see here is the objective response rate. They only saw a response in one patient for 3.7%. This unfortunately did meet futility. And so this study was stopped early. Unfortunately, showing us that we really did not see the activity for TOPO1-80C after TOPO1-80C in this HER2 positive population. We also saw the data that PFS was about 2.3 months. So essentially one scan interval and overall survival was about nine months here in the SETIN study. - And what did we learn from B3, 3, 5, 4? - Yeah, so this was a little bit more complicated. So I'll kind of walk you through here. So over on the left, it was how we initially started the trial. And this was part A. We essentially had HER2 negative disease. So either triple negative or hormone receptor positive, 60 patients, and essentially they were all TOPO1-9EV, except for six patients that had seen a sassy. Then in this lighter shade of pink, we had part B, 20 patients that had HR positive disease, they had all RDC-NATOPO1-80C, or 20 patients with triple negative. Again, had all RDC-NATOPO1-based ADC, or in the dark pink again, part Z, HER2 positive breast cancer, all had already progressed on TREAST-2's amabduruxican. So you have 60 patients, essentially, that were ADC-NATOPO1-9EV, or 61 patients across all three subtypes of breast cancer that had already seen an ADC. And so if we go over to the data on the right, in part A, we saw a pretty good activity. In HR positive breast cancer, we saw a response rate of about 40% and triple negative. We saw a response rate of about 25%. Progression-free survival was almost seven months for HR positive disease in three months for triple negative. But in part B and Z, we saw a very different story. We only saw one response across all three of these buckets, each respectively, for response rate of 5% in each of these categories, and progression-free survival was shorter across the board. 2.5 months, essentially, for HR positive, three months for triple negative, and 1.4 months for HER2. So again, TOPO after TOPO1 really did not give us the same activity that we were seeing in part A, and really echo those same results for SATIN that we were just not seeing activity of TOPO1 ADC after already having another TOPO1 ADC. - Erica, in clinical practice, for that hormone receptor positive, a lower HER2 disease, today we have TDXD based off Destiny Breastle 6, and then Sassi-Tismat thereafter. For triple negative, we switched the sequence where we often use Sassi-Tismat first, and then TDXD if you have lower HER2. Outside trials, based on what we're seeing here, would you add chemotherapy in between before using ADC after ADC, or ADC after ADC is completely a no-go moving forward? - Yeah, I mean, I probably would do chemotherapy. I mean, would you ever use ADC again afterwards? I mean, I think there are certainly circumstances that you would. I mean, we haven't proven that ADC is inferior to chemo. We know from data like tropics, et cetera, that chemo really only gives us a progression free survival of about two months. So, I mean, I think that ADC doesn't beat it. It's probably not inferior, and a lot of our patients do think that ADCs are better tolerated than naked chemo. So I think it is reasonable to use an ADC. It's probably just not performing chemo. I mean, moving along from sequencing of ADC after ADC, same thing here in triple negative breast cancer. What we saw here at ESMO 2026 breast was an update on tropy on breast02 with data DXD, which will very likely get approved here in front line setting along with Sassatusa Mab. With regards to if this was to get approved, how are you going to pick data DXD versus Sassatusa Mab, and what are we learning from this update here? - Yeah, so, Trupi breast02 was our first line of triple negative breast cancer trial for patients where immunotherapy wasn't an option. And what we saw were these secondary endpoints. So, time to deterioration in terms of physical functioning, pain, breast, or arm symptoms, all favored data DXD compared to treatment of physician's choice here. We also saw time to deterioration in terms of global health status and quality of life, and this was statistically significantly improved with data. So, I think just very reassuring data, really telling us how our patients are doing on these antibody drug conjugates. I think in terms of picking between the compounds, I think this is a really individualized decision. I think data, I think Sassi, I think they're really activity wise, providing very good benefit, and honestly providing a very similar benefit. They are different drugs, they have a different schedule. Sassi's day one, day eight, oh, a day 15 off, data is every three weeks, data has more mucus cytos with it, and some eye side effects, Sassi has more count issues, and also has more diarrhea. So, depending on where your patient lives, of what baseline comorbidities that patient has, what side effects they're more tolerant of, I think either could be quite reasonable options. - And another quickly about Sassi's MAB, when we are using this growth factors to help with that count recovery is going to be important with data DXD with mucus cytos, use of that oral steroid mouthwash, hopefully we'll help us get us through that. You know, we keep saying that the field's moving fast, but that is an understatement. We've covered so much here, and this is just from Esmo 2026, and we still have Asco 2026 to go. Erica, thank you so much for walking us through these key studies in recent approvals for our listeners. Let's go over a quick recap. In today's episode with Dr. Erica Hamilton, we started with the recent approval of WebD guest rent from Veritac 2 Study, and how this fits in the evolving ESR1-metaated hormone receptor positive metastatic breast cancer. But with WebD guest rent, let's not forget the importance of monitoring QTC prolongation, though the incidence as low. We then touched on pre-coup error study from Esmo 2026, which continues to highlight the importance of a variant function suppression in pre-menopausal patients, even if oral serds were to become available in early stage hormone receptor positive breast cancer. Robert, your key takeaways for her two disease? Right, Rahul. What we touched on was de-escalation studies. For that T2 note positive disease, we have TCHB in neo-adjuvant settings, which is rather the standard of care. What we saw recently, FDA-approved option of TDXD in neo-adjuvant, as well as adjuvant therapy in her two positive disease got approved. Focusing on de-escalation study, what we have seen from neo-carp and for gain from Esmo, show that image guided and path-ciarguided strategies, which could potentially result in lot less chemotherapy for some selected early stage her two positive disease. And what we also touched on during the conversation was satine and B3354 study with the question, "Can we use antibody drug conjugates after utilization of antibody drug conjugates?" To me, this is not only important for her two disease, but rather throughout the cancer space because ADCs are getting bucket approvals. To close, we touched on recent update from TROPAI on breast O2 looking at data DXT in triple negative disease. And soon we'll have multiple ADCs approved in front-line settings, data DXT and sassy-tism app. And we'll be asking the same question, how do you pick one over the other? But then, can we use another ADC after using one upfront? Satine and B3354 give us some guidance that the data is bleak in these settings. For everyone listening, be sure to check out our other treatment algorithms and conference highlights episodes. We look forward to seeing you soon at ASCO 2020-26. We are at the oncology brothers.