SABCS 2024 Highlights - DESTINY-Breast06, DESTINY-Breast12, PATINA with Dr. Sara Tolaney

Intro Hello and welcome to another episode of the Oncology Brothers Podcast. I'm Rahul Ghosane and with me, as always, is my Co host and brother, Rohit Ghosane. Today, we're excited to dive into some key breast cancer studies from the San Antonio Breast Cancer Symposium 2024. To walk us through this, we're thrilled to have Doctor Sarah Tulaney from Dana Farber Cancer Institute join us. Sarah, thank you so much for joining us. Speaker 2 Oh, thank you very much for having me today, Sarah. Welcome, Sarah. Over next 15 to 20 minutes, we are hoping to cover 3 studies to conclude our series on San Antonio Breast Cancer Symposium 2024. Highlights starting off with Destiny Breast 06 and then switching gears to Destiny Breast 12 and then closing off with a practice changing late breaking abstract patina study. OK, let's dive into Destiny Presto 6, which was first resented at ASCO 2024. Destiny Presto 6 Here we have an update from there, Sarah. Speaker 3 Could you please walk? Speaker 2 Us through the study design and its key findings, yeah. So this data when it came out at OSCO was definitely very exciting and I think practice changing. So this trial was taking patients who had progressed through endocrine therapy and then we're getting randomized as their first chemo agent to get TDXD or to get treatment of Physicians Choice chemotherapy, that being taxane or capsidobine. The trial was a little unique though, because it not just included her 2 low patients, but it also included what we call her 2 ultra low patients, meaning patients who have up to 10% faint staining. So what within the category of her two IC 0, about 2/3 of IC0 patients will have a little bit of her two staining. And so it's that group of patients. So the study was designed to assess the benefits within the HER 2 low population as a primary endpoint, but did include 150 ultra low patients that were included in the overall analysis. And what we saw in this trial was that TDXD did do much better than standard chemotherapy both in the overall population as well as in the HER too low population. And when we look specifically at the ultra low patients, the benefits looked pretty much almost identical to what we saw in the low population. So it did suggest that TDXD in essence does better than chemo with A5 month delta favoring TDXD in terms of progression free survival. But what we saw at San Antonio were the subgroup analysis. And I think this was important because we were trying to understand what are the benefits of TDXD in patients based on other characteristics. So for example, in this trial, you're eligible to go on if you had progressed quickly through a CDK 46 inhibitor. So if you progressed, for example, within six months of your first line treatment with an endocrine agent and a CDK 46 inhibitor, you could go directly onto this trial. You didn't then need to get 2 lines of endocrine therapy before you went on. And so we were curious to know how did TDXD do compared to chemo in those patients who are really endocrine refractory and just blow through their endocrine therapy and CDK 46 inhibitor? And how does that compare to someone who maybe had longer duration benefit on that upfront therapy? And what you saw was that in fact, TDXD has profound benefits in those patients who really are very endocrine refractory because you look at those people who got less than six months on their first line endocrine CDK 4/6, 6 inhibitor, and you see in fact that the hazard ratio is in essence .4. So you're seeing a very large delta, you know, over seven months between the two arms. So even more than we saw in the ITT population. Whereas when you go to the other extreme and you look at the people who are on their upfront therapy for a long time, so more than 12 months now you see that, you know, still TDXT is much better than chemo. The hazard ratio is .67, but the delta again is a little bit less. And then we saw in those patients who really rapidly blew through it. So I guess in my mind, I took this away to say, if someone has highly endocrine refractory disease, we should probably move them on to an antibody drug conjugate and they probably should get TDXT if they're her 2 lower ultra low. So I think this was helpful to see that this is probably someone you don't want to give another line of endocrine therapy to and move on to maybe keep Sidabine. I'd rather move that patient on to TDXT. Speaker 1 Absolutely. This is exciting because we're talking about majority of hormone receptor positive patients fall in this category of ultra low or low classification. And as you've pointed out, the benefit was seen in all courts be it based on tumor burden or their time on CDK 46 inhibitors. And sorry you touched on this, this study is in first line after exposure to endocrine therapy. So a lot of us will be leaning on this once the disease is endocrine resistant. With that said, out in the community, how important is it going to be for us to make sure that the tumor is indeed ultra low her two or have no her two expression at all? How to determine if a tumor is HER2 positive Can we use this in all comers And like 85% of the patients fell in this ultra low, low category. Speaker 2 Yeah. This is a tough question because right now I will say that first we're waiting on the FDA approval for use of TDXD and this first line chemo setting, if you will. And you know how they will make the indication be for low and ultra low. But you're right, this is a tough one because most pathologists are not reading ultra low. You know, usually we follow ASCO kept guidance and so they reported as you know you're either IC zero 1 + 2 + 3 plus and then they test fish if you're equivocal. So our reports generally haven't said if you're IC0 within the zeros. Do you have some level of her two expression? And so unless that changes, it's going to be difficult to actually use this in the community and the ultra low patients. I will say we did have conversations with our pathologists at our institution and they have changed their reports. And now at least at our institution are reporting if they write HC0, they'll then write ultra low. So they'll tell you if it's I null, ultra low one plus or two plus. And so we now know if they're candidate. So I think that's going to have to change to really be able to use this. But you bring up a really good question as well. Would it work in everyone? What if you would it work in a null patient who has absolutely no expression and we don't really know the answer to this question. We had a little suggestion in the Daisy trial where they enrolled zeros and we saw about a 30% response rate, but it wasn't differentiated based on null or ultra low. They did actually show this in their Nature Medicine paper that there were some cases of null patients where they didn't see ADC uptake, but they were seeing activity. And to me it makes me think that there is a little bit of free payload that's probably resulting in activity. And so I think we need more data and there is a trial that actually is now ongoing, Destiny Breast 15, which is enrolling patients who have IHC 0 expression and we'll tease out that null versus ultra low and help us better understand efficacy. But for now I would say we don't have sufficient data to routinely use it in a true null patient. Speaker 1 And this is paradigm shifting because historically her two was positive or negative. Then we started pushing our pathologist saying can you say 1 plus or two plus because of the activity with TDXT here. And now the request says let's talk about ultra low. So keeping our pathology colleagues up to date on this is also equally important. OK, Now moving on to another aspect of trust, Ismabdirectsdcan. Destiny Breast 12 update Its ability to have activity in intracranial disease or to positive disease has the highest incidence when it comes to intracranial disease. With that in mind, Sarah, can you touch on Destiny Breast 12 and its recent updates? Speaker 2 Yeah. So I think this was a really important study. This was actually presented by one of my colleagues, Nancy Lynn at ESMO originally. And this trial specifically had two cohorts of patients. One was a cohort of metastatic, HER 2 positive breast cancer patients that had brain metastases and the other cohort was metastatic HER 2 positive breast cancer without brain metastases. And these were patients who had received up to two lines of systemic therapy in the metastatic setting. And so it was really trying to give us a larger number of patients who had brain Mets and we're trying to understand efficacy of TDXD in this setting. Prior to this trial, we had seen a few small studies that had reported studies like Tuxedo and Debra where we were seeing very robust intracranial objective response rates with DXD and patients with active brain Mets. But the numbers were very small. Most trials were under 50 patients. And so we didn't have large numbers of patients to truly understand what the the benefits were. And in this trial there are about 250 patients on each arm. So this is the largest data set that we have for patients with brain metastases with that second arm really just being a, you know, sort of simultaneously enrolling control to kind of see how efficacy compared to patients who did not have brain metastases. And what we saw was that in fact TDXT does have robust efficacy in the brain. We saw that there was about a 70% endocranial objective response rate, that there is about a 17 month progression free survival and so again very robust activity. 1 cannot cross trial compare the study though to you know, I think everyone in their heads are thinking well how does that compare to her two clients, for example, where we know that Cape sidabine to catnip trastuzumab has robust efficacy in the CNS, but they're very different patient populations. Her decline was more pretreated and so hard to sort of put simultaneously side by side, but nonetheless you're seeing very prolonged PFS more than what we've ever seen in a patient population with brain Mets before and very high intracranial objective response rate. And then at San Antonio, we saw these data with regards to the PR OS and the health related quality of life, really trying to understand what the impact is of TDXD and someone with brain Mets. And then they also looked at it in the cohort without brain Mets. And in fact what they saw was actually similar results in both cohorts. So that if you looked at deterioration free rates at 12 months, they were over 50% for cognitive, emotional, physical, social functioning and global health related quality of life. So really suggesting that you know we are not having significant deterioration in Qol in either arm. So I think very important and data not only is it efficacious but generally not having a significant impact on quality of life either. Thanks for covering that Sarah, especially these trials her to climb along with TDXD. These are commendable to include brain metastatic patients because these are poor prognostic markers and they are usually not included. So having that evidence of intracranial activity and enrolling these patients in clinical trial is vital. And also to see that quality of life is not being compromised is important as well. Though we have been able to extend the survival but important is the quality of life data. Now with the intracranial disease as you mentioned that we have two viable options that is TDXD or to catnip braced regimen. Intracranial disease Sir, how are you maneuvering through in terms of sequencing? Are you relying on TDXD? Though again, I don't want to harp on the cross trial comparison here. Speaker 3 But what is your? Speaker 2 Sequencing here. Yeah, that's a, it's a really good question. So I'll say currently we are using THP in the first line setting and we'll I know talk a little bit more about that first line setting based on some data that came out at San Antonio. And then after progression, we'll usually use TDXD based on Destiny breast O3, which in fact showed us that you get about a 28 month progression free survival with TDXD in that second line population. So the question then comes up, well, what if you have someone who has brain metastases after THP? Are you gonna choose her to climb or are you gonna choose TDXD? And you know, I don't want to say there's a wrong or a right answer, but I will say generally my preference is TDXD even for the brain met patients because the PFS that we're seeing is really unprecedented. Again, we've never seen 17 month PFS and embracement population. We've never seen 28 month PFS in the metastatic her 2 positive setting in a pretreated population. So, you know, I, I think it's hard to beat. And so I, I think I just feel comfortable using it in that setting, you know, so I make a decision about whether or not I want to give local therapy first. If someone has one or two lesions that are easily, you know, radiated with SRS, they'll do that. And then if they've had systemic progression, then usually to move them on to TDXD. But you can also think about treating patients without doing local therapy with TDXD since it does have robust activity and carefully following both systemically and the CNS. Speaker 1 Rohit, often our patients are asking am I living longer and am I going to live better? Most of the drugs offer one or the other here with TDXD health quality outcomes and the PFS. We've seen both that, at least in my practice, Sarah, that has been my sequence, exposing them to TDXD and then relying on Katynip Cape site to be in combinations. Speaker 2 A good point about the quality of life issue too, because it, yeah, there are side effects of TDXDI, don't want to downplay that. But at the same time, it has such impact with efficacy that I think patients symptoms actually get so much better because they have less tumor burden and they're they're feeling better, which is important, right? At the end of the day, we cannot forgo the ILD that comes along with it, alopecia, GI side effects. So again, putting all quality of life and survival data in pack together, now moving. Practice-Changing Patina Trial Along into our last study. Speaker 2 Which is in fact practice changing patina. Speaker 3 Trial which is for triple. Speaker 2 Positive metastatic disease. Speaker 3 Sarah, could you please go over the? Speaker 2 Study design and findings here Yeah this was a surprise presentation at San Antonio where the study team just got these data a week before they presented It's a very impressive yet again San Antonio pulled off a very late breaker into the program but exciting. So this study took patients who have ER positive, her 2 positive breast cancer and they had undergone induction chemo with dual her two directed therapy in essence. And so for example, the way we give induction THP a la Cleopatra, we usually give 6 to 8 cycles. We for those patients who respond to therapy or have stable disease, we often will stop the chemo and put them on their HP maintenance. For those patients who have your positive disease, we usually add endocrine therapy to that backbone. So this study saying for those patients that would normally go on to get HP endocrine therapy, we're going to randomize them to get that with or without pelvic cyclib. With the idea being that we had known that CDK 46 inhibition has activity not just an ER positive, her two negative disease. But we had seen now several studies that have shown activity in ER positive, her 2 positive breast cancer. And so the thought was, could you use it as a maintenance strategy to really extend the time of Disease Control? And so this study was designed to look at progression free survival. But important to note, they started their clock at the time of randomization. So it didn't start at the time of initiation of chemo. It was after the chemo induction that people were randomized. And then we're looking at progression free survival from that point forward. So with the maintenance portion forward and what we saw, I will say really surprised me because if you look at the control arm here, So again, people getting HP, the endocrine therapy, you're seeing a progression free survival of 29 months. So remember if you go back to Cleopatra and you look at people who got THP and then went on to HP maintenance, they did not get endocrine therapy and Cleopatra. So the year positive subgroup did not get endocrine treatment and their progression free survival overall was around 18 months. And I would also remember that in Cleopatra, only 10% of patients had seen prior trastuzum of in the early stage setting, where in this trial 70% of patients had seen trastuzum of based therapy in the early disease setting. So this is a different patient population and we're seeing a very different control performance. But I would also caution that I think the reason we see the control do so well and this was pointed out very nicely by Sarah Hervitz in her discussion was that they kind of passed a test, right? They had to get through 6 to 8 cycles of chemo and not progress. And so we took the good actors, the people who are very her too sensitive and would do well and then we randomized them. So again, we, we selected out those patients And again, I think that's why we see the, the control do so well, but then you're seeing a 15 month delta in terms of improvement. So the PFS in the intervention arm was 44 months. Again, really blew it out of the waters. I'll say this is something I've not seen before in a first line population. So I think definitely practice changing and would suggest that if you had an ER positive, her 2 positive patient who gets through induction chemo with HP and does well, then you should shift them on to to HP maintenance with endocrine therapy and CDK 46 inhibition and then and really should become a new standard of care option. Speaker 1 You know, can we take a minute to appreciate how impressive it is that on metastatic disease, first line patients are living close to four years? Treatment Algorithm for Triple-Positive Disease This is very impressive, Sarah. We've been talking about Trustezmatorextcan in previous two studies and we see that this continues to move earlier and earlier. You're leading this effort on Destiny Breast O 9 now with data of patina in hand. If both were to become available, what will be your treatment algorithm in this triple positive disease look like? Speaker 2 And now that is a good question. And so I think we're we're anticipating we could see data from Destiny Breast O 9 next year. That study had looked at TDXD with or without pertuzumab and compared it to THP. But I think as you're alluding to in that trial, there was no maintenance strategy. They just gave TDXD until time of progression. So you could imagine, you know, let's say the PFS ends up being in the 30 ish month range, 3336 whatever months if we want to guess that means that people are on TDXD for you know, three years potentially right until they progress. And so, you know, the question I think now is going to be if that study is positive and, and shows a very robust PFS, could we then think about moving to an induction maintenance strategy where maybe you give TXD upfront, maybe the same 6 to 8 cycles and then you move on to HP maintenance, endocrine therapy in the air positive patients, for example, with the CDK. So there is a study that's actually ongoing called the Demeter trial where they are giving upfront 6 cycles of TDXD and then they're following that with HP maintenance just as a single arm study. So it's, you know, a small phase two experience, but that will at least give us some initial data for that type of a strategy. So I think we'll need to do more work here to move towards that kind of a strategy. But I think that's what we'd all love to see is, you know, potentially induction TDXD. Followed by maintenance would really be nice. Speaker 1 And Sarah, just before we wrap up, last question, this study was with pablocyclib. Is pablocyclib the right CDK46 inhibitor for this patient population? Would you lean towards abema or ribocyclib in this particular patient population? We also saw a retrospective study where all three CDK 46 inhibitors had very similar outcomes in real world. So if you are going to lean into CDK 46 inhibitor in this particular patient population, is pablocyclib the right agent or Abama or Ribo? Speaker 2 Yeah, no good question in the ER positive, her two negative diseases keeps getting discussed, right? Because as you pointed out at San Antonio this year, there was some really nice real world data showing OS was actually very similar across all three agents. I think here though, the question is a little different because we are combining with trustezumab and pertuzumab. And so I think you bring up a good point, which is actually you should not use abemaciclib in this setting because we actually had done a phase one trial looking at combining ABEMA with HP. And we did actually see quite a bit of GI toxicity as you could imagine, given that both pertuzumumab and ABEMA do 'cause diarrhea. So I would say I would stick with the pelviciciclib given that that's what was studied here. There is safety data however, and and actually a very nice study done with ribocyclib in this setting. And so you know if someone had an issue with Palbo and you needed to switch them to Ribo for some reason, I think it would be OK because there's safety. But certainly I think the choice here is Palbo. We have a phase three trial showing efficacy and we have very robust safety data. Thanks for covering that, Sarah. Patina is indeed practice changing given such a dramatic PFS improvement. We'll get eagerly await TDXT data in frontline settings though as you pointed out, Sarah, that this data is with Palbo, there are some safety concerns with ABEMA and again not well established with RIBO. So for now, continue to utilize this with Palbo Cyclip. Sarah, thank you so much for taking the time to go over these important practice changing abstracts from San Antonio Breast Cancer Symposium 2024 with us. Summary For our listeners, let us go over a quick recap. Speaker 3 Rahul, we've now wrapped up our series for San Antonio Breast Cancer Symposium 2024. Highlights. Speaker 1 Yeah, over the three episodes, Rohit, we've covered 10 studies from SABCS 2024 today with Doctor Sarah Tulaney from Dana Farber Cancer Institute. Our focus was on Destiny Breast O 6, Destiny Breast 12 and Patina Trial. There is a lot to unpack here, Rohit. What are you going to put into practice based on what you've heard today? Speaker 2 And the TDXD is clearly an active agent including its ability to respond to intracranial disease and then again sequencing it with to catnip there on though we eagerly await for Destiny breast 09 for TDXD in early line for hormone receptor positive and her 2 positive disease. But at least at this time we have patina trial with THP followed by CDK 46 inhibitors and endocrine therapy, which is palbociclib, which again appears very promising based on PFS data. Thanks for joining us. Make sure. Speaker 3 To check out our. Speaker 2 Other conference highlights, treatment algorithms and recent FDA approval discussions. We are the oncology brothers.