ASCO 2025 - Breast Cancer Highlights: INAVO120, SERENA-6, VERITAC-2, DESTINY-Breast09, ASCENT-04

Intro Hello, and welcome back to the Oncology Brothers Podcast. I'm Rahul Hussain. As always, I'm here with my brother and Co host, Rohit Hussain. We're thrilled to bring you the latest from the ASCO 2025 Annual meeting with thousands of abstracts represented. And today we're focusing on breast cancer and we have narrowed it down to five important abstracts. To cover this, we're excited to have Doctor Erica Hamilton from Sarah Cannon Research Institute, who is also the Scientific Committee Chair for ASCO 2025 meeting. Erica, congratulations on an outstanding ASCO and thank you for being here today. Speaker 2 Thanks, I'm happy to join you guys. Speaker 3 Wow Erica, congratulations again. ASCO 2025 was a huge success as we saw quite a few practice changing studies focusing on breast cancer arena. Here hormone receptor positive space we'll talk about in novel 120, Serena 6 and Varitek 2 and in her two positive space we'll cover Destiny breast O 9 and closing off with ascent O4 from triple negative breast cancer. Before we kick off with in novel 120, I do want to read right updated data that we saw from soft and textile with ovarian suppression with aromatase inhibitor in high risk pre menopausal women, which ends up being the treatment of choice given improved breast cancer free interval and overall survival. OK, now on to in Nava 120. InnateN120 In Nava, LISIB was approved back in October 2024 for patients with pick three CA mutated disease that had recurrence on or after completing their adjuvant endocrine therapy within 12 months. So of very high risk population. Erica, can you please start us off here with study and its findings? Speaker 2 Yeah, absolutely. So this was a pretty straightforward design randomization 1 to one in the first line space, so different than we see with other PI3 or AKT where we're really talking about post CDK. So this was a full vestrant Pablocyclib loan or full vestrant Pablocyclib with Anavolisib and everyone had PI3 alterations. But what's really unique here is that they had to have progressed within 12 months or while on their adjuvant AI. And remember when we look at these results that the FDA pulled analysis for all three of the CDK 4 sixes showed that patients just with API 3 alteration are not a set of patients that we actually worry about their benefit from CDK. So what's unique about this population is really that quick relapse from the adjuvant setting, progression free survival is more than doubled, almost tripled. 7.3 months with fulvestrant and CDK alone, 17.2 months with an avalicid, we should be getting around 20 months typically on a CDK 46 inhibitor. Patients that relapsed early from adjuvant AI in the absence of API 3, they're only having APFS of seven months. So this is really an exceedingly poor risk patient group. So definitely encouraging to see that 17 months, that's more in line of what we would expect from first line treatment for patients with ER positive breast cancer. Also overall survival, certainly our gold standard here we saw 20-7 months without an Avolisib, 34 months with so essentially A7 month benefit and the P value was 0.01. Speaker 1 So again, not a list of this first in class to show overall survival benefit, but when we're talking about this class of drug, we have to keep hyperglycemia in mind. This is a class effect. And again, Rohit, you touched on this, Erica, you brought this up as well. This is high risk patient and we are seeing overall survival benefits. So this is meaningful, but we have to do better on our end to make sure we're getting through the side effects. OK. Sticking with metastatic hormone receptive positive disease, our current standard of care here is CDK, four O 6 inhibitors with endocrine therapy. ESR1 mutations and chemiseptrant And then we start to look for some actionable mutations, particularly ESR one mutation or AKT pathway mutations. But in Serena, 6/1 of the plenary discussions, we were looking for a serial NGS for ESR, one mutation, A resistant mutation and then there was a switch to chemisestrant before there was an actual progression of disease on scans. Erica, can you touch on this strategy? And is this ready for prime time? Are we really changing the biology by hitting the disease early? Importantly, are patients living longer with us? Speaker 2 Yeah, I think you hit on exactly the questions we're asking ourselves. This was plenary. It's certainly a proof of principle for Cami. Zestrant, you brought up the big questions here really around PFS 2 and are people living longer. This is a paradigm shifting idea for breast oncology that we would use the emergence of resistance marker like ESR one in the absence of progression to potentially change therapy. These patients were on AI and CDK 46, drawn every two to three months. If they popped positive for an ESR one mutation, that's hinting to us that we're going to see progression soon. They did have scans. They didn't have progression at that time. They were randomized 1 to one, either continuing their AICDK or moving to CAMI. Zestrinth oral served with CDK. Speaker 1 And again, here we're looking at PFS and PFS 2, but we have to be careful with this PFS 2. Speaker 2 Absolutely. PFS, not surprisingly, definitely longer 9.2 months with continuing your AI and CDK 46. Another little thing that I gleaned from that is the average time, if somebody has a resistance mechanism and a new CTD day finding like this that it may take them to progress and that's another nine months. Cami Zestrant clearly doing much better here at 16 months progression free survival too. Was trying to get at the question of, okay, well, you know, that arm that switched, switched therapy. So they kind of had two arms at that. I mean 2 treatments at that point and the other arm stayed on their one treatment. So it's not really comparing apples to apples. It's comparing a little bit 2 lines of therapy versus one line of therapy, albeit in the absence of progression. And so progression free survival looked at that next line and that was longer. So you know, at 12 months, 85.4% of patients on CAMI Zestra at CDK remaining progression free, 74% on the AI and CDK. There was a great discussion by Doctor Dean Michelle here at ASCO that it's not necessarily a completely fair analysis at this point with that second line, we're almost comparing 3 lines of treatment to two lines of treatment. So I think a lot of us think that yes, this probably is coming. Is it prime time ready today? No, I don't think so. I think ultimately if we're going to do this for patients and you know the call cost and having to draw this every two to three months, I want to tell them that they're going to do better down the road based on this, they're going to live longer, that we're going to be preventing some type of new metastasis like a liver met where they're going to be living better. And we don't quite have the data to do that yet. Speaker 3 Right, I totally agree, a great idea especially making personalized treatment which started earlier. But we do need longer term data before we all adapt. This are in our practice OK, while talking about ESR one mutation space. Varitek-2 Trial Now let's shift to Varitek 2 trial. Erica, you led this trial for a protech estrogen receptor degrader compared comparing here to full vestrant in ER positive her two negative advanced breast cancer. Erica, what did the data show particularly for ESR one population If this gets approved, this will be in the same space as LSS trend. Where would you see this fit in your practice? Speaker 2 Yeah, so absolutely conflict of interest. I'm the one that presented this. This was a straightforward design. Everyone had to have had endocrine therapy with ACDK 46 inhibitor. So very real world population. They could have had up to one additional line of endocrine therapy and patients were not allowed to have prior fulvestrant since it was the control arm or prior chemotherapy. We also wanted to make sure that these were patients that were reasonable to go on to further endocrine therapy. So they had to have benefit for their last line of endocrine therapy for at least six months. So comparing fulvestrant which is intramuscular twice in the first month and then monthly thereafter versus vegastrant which is a once a day oral medication. So if we move over to the data, essentially our primary endpoint was progression free survival in those patients with ESR 1 mutations. And if that was positive, then we would go on to test PFS in intention to treat all comers regardless of mutations. And in fact, Bebdegestrint did both statistically significantly and in my opinion clinically meaningful prolongation of progression free survival five months versus 2.1 months. I always like to look at the control arm. Is it what we would have expected? Absolutely. Fulvestrate 2.1 months is very in line with what we saw with the Emerald study of LS Estrint, right at 1.9 months, exactly what we would have expected. And remember that the Emerald study, everyone had seen a CDK. Now if we want to compare it to Ilunestrin, that's where it gets a little bit tricky because that was not an apples to apples. About 30% of those patients with ESR one mutations had not seen a CDK. That's why you see a little bit longer PFS in both arms, including the fulvestrin arm with Ilunestrin. But I think we we can compare this to LSestrin when we looked at progression free survival in all patients, no difference. So like we've seen with other drugs, the benefit was really among those patients that had ESR 1 mutations. Speaker 1 Erica, can I push you a little more on this? If this becomes available, where would you use this? Who's the right patient? Speaker 2 I I would use this second line for patients with ESR one mutation. We all dread the cross trial comparison. We all secretly somewhat do it as well. So if we look at the Emerald data, if it was 1.9 versus 3.8 months for patients that had ESR one mutations, the full vestrant arm is, you know, comparing quite the same. And so you know, perhaps Vepdegastriate's a little bit better since we're getting five months. I certainly don't think it's worse. You know, the other thing that stood out to me about this trial was the tolerability for some of the drugs in the oral cert class. Gastrointestinal side effects can be a bigger deal for patients. Nausea, vomiting, diarrhea. We saw very little of that with that degustrade. In fact, the most common side effect was fatigue. All grades, 27% of patients. So said another way, three out of four patients didn't complain of any fatigue. And then second and third side effects were LFTS and nausea, but both of those, again any grade were in the low teens, less than 15%. What did not show up on our adverse event table was vomiting or diarrhea because across any grade that was only 6%, I really don't think that that's a signal that we need to worry about with this drug. So I'm happy with the activity and I'm very happy with the tolerability. Speaker 1 You know, ESR one mutated space, we've seen this even with Serena, it's starting to get crowded. We're seeing these agents move earlier and along with that with combination. OK, let's move on to her 2 positive space here, metastatic breast cancer and we're looking at much awaited Destiny Breast O 9 trial. Metastatic Breast Cancer Just looked into TDXT with predtisumab with standard of care. They're taxane trustees mouth and pretis mouth. Speaker 2 Yeah, this thing begins the section of your talk from The Jeffersons moving on up. Every time I think about this or the Ascent trial, I have that song playing in my head. You're right. The antibody drug conjugates have kind of taken breast cancer by storm labor of moving these drugs up into the earlier and earlier line settings. Destiny breast O 9 was first line. Her 2 positive breast cancer comes after DBO 3, kind of making this the standard in this second line setting had a little bit of an interesting design because of our benefit with pertuzumab in this setting. So we had our kind of classic taxane with trastuzumab and pertuzumab or grey arm. Then we had trastuzumab drugs decan alone, but then also this bonus arm with trastuzumab drugs decan plus pertuzumab. What we're presenting here is only the TDXD plus protuzumab arm. We don't have data from the TDXD alone, so we can't answer the question right now. Does pertuzumab add anything substantial to TDXD? What we can say was that TDXD plus pertuzumab easily beat chemo plus tretuzumab and pertuzumab. So progression free survival was lengthened from right at about 27 months or a little over 2 years with taxane tretuzumab, pertuzumab to almost 41 months. So the benefit the delta here is about 13 months. So over a year improvement in patients remaining progression free. Certainly I think it's a little too early to see overall survival. This curve was shown. It was not significant at the time, but we know that our her 2 positive patients are doing well and have a good long overall survival. So I'm not surprised that we didn't see that yet. Speaker 1 I'm going to sound like a broken record, Erica. What does this mean for our clinical practice? What does it really mean for us today in our clinical practice? Are you going to use this just for induction? Are you going to use this only for high tumor burden, only for CNS disease? What are you going to do today? Speaker 3 Especially when it's just like lifelong chemotherapy type side effects. Speaker 2 Yeah, absolutely. I think you guys her normal hit on the very appropriate question. I think the data is really compelling. So yes, I am planning to use it first line. The bigger question is am I planning to just continue it indefinitely 3 to 4 years? And no, I can't say that I am the advantage. The thing we liked about the taxane trust, tuzumab or tuzumab is that we really treated for a number of cycles, 6 to 8 cycles and then the chemo stopped and they were just on antibody maintenance. And so that led to a good quality of life for our patients and you know, kind of not beating them over the head with chemotherapy for too long. I think that there's gonna be a big desire for a maintenance strategy here. The question is, what is that maintenance strategy really gonna look like? Now remember that we also have patina data showing that a CDK 46 inhibitor was very helpful in this space for patients that had the ER positive. I think you're gonna see a lot of people treating with trastuzumab drugs to can for a certain amount of time, stopping that and then moving to HP maintenance or HP endocrine therapy and ACDK per per patina. The question we don't have the answer to is, is there a population that it's not appropriate to do that for? So for example, you know, if somebody only gets stable disease and they're not maybe having a great response, that's probably not somebody that's gonna do well on trastuzumab drugs to can for a long time. So the type of trial that I'd love to see is, you know, somebody that maybe had a very good partial response, 50 or 70% stopping that patient after several months and maybe not stopping the patients that are showing us that they're not responding really briskly to trastuzumab drugs to can. I think I would plan to do at least 6 state cycles if I could. I think my strategy, again, completely absence of data, this is just my personal opinion, is that I'm probably going to treat to a maximal response. So as long as those scans are still showing shrinkage, I'm probably going to treat as long as people are tolerating it and can get more. And then once we stall at that maximal response, that's probably the time that I'm going to think about pulling it away. So if somebody's tolerating well and their cancer is still shrinking, I'd be willing to go to 10 cycles, etcetera, but I'm probably not going to give three or four years. Speaker 3 So indeed, patient shared decision making is going to be the key, especially when again the side effect profile is very similar to chemotherapy with ILD, alopecia, fatigue, nausea and two deaths associated with this in this trial. OK. Now moving along into the triple negative space where we have the data from Ascent O4 where sassatuzumab, yet another ADC was tested with pembrolism map in PDL 1 positive case, which is CPS more than or equal to 10 compared to chemo with pembro. Erica, your thoughts here? Speaker 2 Yeah. So the second of our moving on up, so straightforward design chemotherapy and you have your choice of paclitaxel, nab paclitaxel or the gym side of beating carboplatin combo with pembro versus sasituzumab Gobatekin. Straightforward Design Chemotherapy All of these have a little bit of a different schedule. Sasituzumab is the day one and day 8 every 21 days. And again, completely correct that this is for that subset of patients that are PDL 1 positive and that tends to be about 35% of our triple negative patients in the first line probably. So what we saw was a lengthening of progression free survival, 7.8 months with chemo plus pembro and 11.2 months with sasatuzumab, gobatekin and pembro. I think that this is really a very easy sell. Our patients with triple negative breast cancer are not doing as well as our her two patients or HR positive patients. This is not incredibly long. So I really can't think of a whole lot of reasons that I wouldn't want to offer my patients sasatuzumab with pembro here. Obviously we don't see any overall survival yet. But I'll also maybe throw a teaser out there that we have seen a press release that the companion trial to this Ascent O3 was also positive. And so that was the trial for the PDL one negative patients. So straight up chemo versus sasatuzumab Govatekan in first line triple negative. So we anticipate to see results of that at ESMO. So I suspect we don't have FDA approval yet, but I suspect we're going to see some of these changes over the next year in guidelines etcetera. Most of our first line triple negative patients are going to be receiving ADC. Speaker 1 And again, the reason why you're saying it's an easy sell because triple negative is such an unforgiving disease. So we want to make sure we're attacking this upfront, aggressively. Absolutely. Side effects of pembrolizumab Erica, touching about touching on some side effects that we have to worry about diarrhea, neutropenia now with pembrolizumab, Pembrolizumab in itself can cause diarrhea. So there's some overlap side effects here. How are you going to decipher which ones which? And then can you also touch on both factors here? Speaker 2 Yeah, I think very pertinent questions. You know, interestingly enough, when we looked at the adverse events, saskatusumab actually compared quite favorably to chemo. So you know, chemo certainly can cause neuropathy, it certainly can also cause neutropenia. So neutropenia really with both. The challenge with saskatusumab really is that day one, day 8 administration and you have a couple choices. I think pretty much universally, I'm giving a long acting growth factor after that day 8 to try to boost the counts up high enough that we can kind of ride them through for the next cycle. Because you can't give, you know, a PEG fill Grastom after day one because you're coming in with chemo on day 8. That works for some patients. For patients that it doesn't, I try to give short acting Neupogen for, you know, it's very funny what you can get approved. I remember we used to be able to send people home with syringes all the time and then we got into this period where I had a lot of trouble having insurance cover that an hour back into a time where I've been very successful over the past year getting that for patients to have administration at home, which is much more convenient. So I do that. And then if we can't get the growth factor or we're having problems, I think about a dose reduction or an altering schedule where you could actually think about giving day one day 15 instead of day one. Day 8 has not been studied, but people are are doing that sometimes when they're forced to. I think also diarrhea. Great point. We definitely see that with sasatuzumab Govatekin. I find the diarrhea very binary. People either have it and they really have it or they don't have it at all. I'm always amazed by the patients coming in saying I don't have diarrhea at all. Right. So very different than Tkis where people are kind of universally going to get diarrhea. It's just a question of how bad. I think in terms of kind of how am I going to tease out if it's pembro, you know the diarrhea from sasatuzumab is going to start from the beginning. So it would really be a change in the characteristic of that diarrhea that would probably Alert me to thinking about pembro or immunotherapy related diarrhea. Speaker 1 Absolutely. And again, there's a theme here. I set this for the novelist, that same story with sasatuzumab. We're going to use these drugs. We have to get comfortable in managing these side effects and make sure our patients are safe on these drugs. Erica, we've covered a lot in a short time. Thank you so much for walking us through these key studies. And again, congratulations for an amazing ASCO 2025 for our listeners. Let's go over a quick recap in this episode with Doctor Erica Hamilton. Recap We've covered five key abstracts in breast cancer from ASCO 2025, 1st in Nova 120, which showed promising overall survival data with in Novolocyte plus Polycyclip and philvestrin and pick three CA mutated hormone receptor positive. Her two negative advanced breast cancer of 34 months versus 27 months. Serena 6A plenary highlight demonstrated improved progression free survival with chemisestrin and CDK 46 inhibitors. An emerging ESR one mutated disease versus waiting for disease to progress here. We need more mature data before we widely adapt this strategy for all our patients. Speaker 3 Then Veritec 2 highlighted a vet digestrint superior PFS or fulvestrant in ER positive her two negative breast cancer especially in ESR one mutated patients. This is a new class of drugs that seem to be very well tolerated. If approved, this will be in the same space as LSSS trend. Then in Destiny breast O 9, we discussed TDXD plus pertusumab significantly improving PFS in frontline HER 2 positive metastatic breast cancer challenging the Cleopatra regimen. Finally, Ascent O4 sassatusumab with pembrolizumab in PDL 1 positive showed improved PFS benefit with sassatusumab. Govitican. Thanks for joining us. Make sure to check out our other discussions, including treatment algorithms, recent approvals, and conference highlights. We are the oncology brothers.