Report Back from ASCO 2024: Latest Updates on Metastatic Breast Cancer (MBC)
July 12, 2024
Would you like to have a better understanding of the new research and treatment in metastatic breast cancer? Join Dr. Kevin Kalinsky, breast oncologist and researcher from Emory Winship Cancer Institute, to learn about the latest updates from The American Society of Clinical Oncology (ASCO) annual meeting 2024. Dr. Kalinsky, discusses the new research presented at the conference and answer questions you may have.
Key Takeaways From Webinar:
- Enhertu (T-Dxd): This drug is now an option for treating HR+, HER2-low, and HER2 ultra-low metastatic breast cancer (MBC).
- Switching CDK Inhibitors: For individuals diagnosed with HR+ HER2- subtype on first-line therapy with a CDK4/6 inhibitor plus endocrine treatment, switching CDK inhibitors plus fulvestrant after progression can be beneficial, especially if there is no targetable mutation.
- Tumor Detection: Slower-growing tumors may not shed ctDNA, leading to a negative liquid biopsy. In these cases, a tissue biopsy may be necessary.
00:00:00:00 - 00:00:27:19
Unknown
Hello and welcome to today's webinar. Report back from ASCO 2020 for latest updates on metastatic also known as stage four breast cancer. I'm Kate Viera Pfitzer, the Metastatic Breast Cancer Program Director at SHARE. And I'm Victoria Goldberg. I'm the host and producer of the podcast Our MBC Life. Before the presentation begins, I'd like to tell you a little bit about Share.
00:00:27:21 - 00:00:56:21
Unknown
Share is a national nonprofit that supports, educates and empowers anyone diagnosed with breast gynecological cancers and provides outreach to the general public about signs and symptoms because no one should have to face breast, ovarian, uterine, cervical or metastatic breast cancer alone. For more information about our upcoming webinars support groups and help line, please visit our website at sharecancersupport.org
00:00:57:07 - 00:01:27:24
Unknown
We're very excited to have Dr. Kalinsky join us today as a speaker. And now I'd like to hand it over to Dr. Kalinsky to introduce himself. Hi everybody. Thank you so much for the invitation. It's a great program. Happy to just be involved. I see a number of familiar names as participants, and it's nice to see you virtually, some of whom it's been some time.
00:01:28:01 - 00:01:50:19
Unknown
I am a breast milk oncologist, have been at Emory now for about four years and came down here to direct the breast cancer program And then most recently for the last 102 days, I had been serving as the new division director of medical oncology here at Emory.
00:01:50:21 - 00:02:18:18
Unknown
I'm going to share my slides before we go. Hopefully you can see this. Can you? One second. I go here. Great. All right. So for the next 35 or so minutes, I'm going to give updates from what we saw at ASCO and I'm going to talk about at least two trials. We will see how we are doing on time.
00:02:18:20 - 00:02:53:22
Unknown
There's a third study that I also included, but again, I may to start early and take your questions because I want to make sure that we have time to really go through the questions that you may have after the first two studies. These are my disclosures. So I'm going to talk about first what I think the most highly anticipated study was at ASCO 2024, and that was the Destiny Breast six study for those who were in attendance at ASCO.
00:02:53:23 - 00:03:43:05
Unknown
There was a special session. There was added to the ASCO event to the itinerary so that we could have time to talk about this particular study. So Destiny Bristow, six, is looking at patients with hormone receptor positive her to know or ultralow metastatic breast cancer who had received prior endocrine therapy. So just to give a bit of background, when I was a trainee and also not all that long ago, we would really think about tumors as being either HER2 positive or to negative.
00:03:43:07 - 00:04:20:09
Unknown
And so if one had a tumor that was and we score this one 0 to 3, and if it was three, it was positive and if it was one or two, we would do additional testing with oftentimes something that's called this and that would determine whether a patient had her to negative or HER2 positive breast cancer. So again, if it was her two, three plus or if it was fish positive, it was HER2 positive, if it was anything else, it was consider her to negative.
00:04:20:11 - 00:04:54:24
Unknown
But then we saw at ASCO about two years ago that four patients who had her two one plus or her two two plus not amplified, meaning the fish was negative. We actually now call those HER2 low and we saw it's a new Mody presented at ASCO two years ago than now for patients with metastatic hormone receptor positive for two low breast cancer that we have benefit from giving trastuzumab direct to.
00:04:55:00 - 00:05:32:08
Unknown
Again that is essentially it's also called TD D and is essentially Herceptin that is linked to a chemotherapy. And again, this is a drug that is approved for HER2 positive and for her to low breast cancer and part of what was being evaluated in the study. So the study was evaluating two things. The first thing was if a breast cancer was HER2 ultra low, meaning it wasn't zero, but there was a little bit of staining, it just hadn't reached the one plus threshold.
00:05:32:10 - 00:05:52:02
Unknown
Was there a benefit of giving the drug? And then the second thing is what if we gave the drug a little bit sooner? Because right now we often give the drug after patients have had a line of chemotherapy in the metastatic setting. But the question of this study was what if you gave it earlier? So it's looking at those two things.
00:05:52:02 - 00:06:21:21
Unknown
What about ultralow and what about if you gave it earlier? So the design of this study, all of these patients had hormone receptor positive breast cancer. All of the tumors were either HER2 low. Again, that's defined as one plus or two plus and this negative or HER2 ultra low. Again, not quite one plus, but with a little bit of staining.
00:06:21:23 - 00:07:04:03
Unknown
None of these patients had chemotherapy in the metastatic setting. All right. So all of these patients had some prior endocrine therapy like Anastrozole or Letrozole or faster index, i.e., Fulvestrant. And a number of these patients also had prior CDK4 six inhibitors like palbociclib or RIBOCICLIB or abemaciclib. Okay. So in this study, patients were randomly assigned, had a 5050 chance to either get tricky, which is given once every three weeks versus physician choice chemotherapy.
00:07:04:05 - 00:07:41:16
Unknown
And those options were either side of being or paclitaxel, whether that was nab paclitaxel or general paclitaxel and the primary endpoint of the study, the thing that they were looking at was did it take longer for cancer to progress? If patients received chemotherapy compared to if they reacted? And so they looked at that HER2 low population. And again, there's a small proportion of patients who had her to ultra low disease.
00:07:41:18 - 00:07:53:04
Unknown
So know that some of these slides have a good amount of information, but I'm going to really try to break it down to the critical piece.
00:07:53:06 - 00:08:03:19
Unknown
So the median age of this study was about 60.
00:08:03:21 - 00:08:32:21
Unknown
All of the patients for the most part, were women, and the percentage of patients was about 20% who had four to ultra low disease. So, again, the majority of patients had her too low, but there was a small proportion who had her to ultra low. All of these patients had estrogen receptor positive breast cancer for the most part.
00:08:32:21 - 00:09:01:14
Unknown
There were some just a few that have progesterone receptor positive breast cancer. The one thing to know about this study is that few patients had only breast cancer that had spread to the bone. The majority of patients had involvement of visceral organs like liver or like the lungs. So about two thirds of patients had liver involvement when they participated in the study.
00:09:01:16 - 00:09:36:05
Unknown
In terms of how many prior lines of endocrine treatment patients had had in the metastatic setting, like Anastrozole or Letrozole or Plasma Dex or L assessment, for instance, the median number was to about 50% of patients had received only endocrine therapy without another targeted therapy as one of their prior lines. You can see that 90% of patients received prior CDK4 six inhibitors like abemaciclib or like RIBOCICLIB.
00:09:36:07 - 00:10:02:10
Unknown
The other thing that's worth noting is that about two thirds or so of patients also had endocrine therapy in the early stage setting. So this was the primary endpoint that they were looking at. All right. And so what you're looking at here is what oncologists like to call kaplan-meier curves and what you're looking at in the access here.
00:10:02:10 - 00:10:39:13
Unknown
I don't think that you can see my cursor, but one of that at the bottom you're looking at how long were the patients on this therapy in terms of months. And then that top part is just looking at how long was it taking for cancer to progress. And you can see that in blue that those are the patients who had been randomly assigned to to take that the time that it took the median, the time that it took for patients to have tumors that had progressed on to D was about 13 months.
00:10:39:13 - 00:11:02:21
Unknown
There were some patients that were shorter, some patients that were longer, but this was the median in terms of physician choice, chemotherapy, again, drugs like side of being or paclitaxel, that was about eight months. So there's about a five month delta in terms of how long it took for these tumors to progress. And this was statistically significant. Right.
00:11:02:21 - 00:11:25:00
Unknown
So the moral of the story, what I'm showing from this slide is that patients that were randomly assigned to tDCS D did better than are standard chemotherapy. And what I like to say to patients is the way that tDCS works is like a GPS drug, right? So it's targeting HER2, but the way that your GPS tells you where to go is the way that this drug works.
00:11:25:00 - 00:11:35:05
Unknown
It essentially targets HER2 and then directly delivers chemo to the cancer. So.
00:11:35:07 - 00:12:02:06
Unknown
And what you're looking at here is they also had radiologists study radiologists that looked at the time point that it might have seen that these tumors were progressing and the data looked the same. Right? It was a difference of 13 months and those who were randomly assigned to two D versus of eight months for those who had standard chemotherapy.
00:12:02:08 - 00:12:31:18
Unknown
So again, those were patients focusing on patients who had her to low breast cancer. But there was about 20% of patients who had HER2 ultra low disease, and the results looked very similar, right, where you saw this delta of difference between those who had randomly assigned to t d it looks the same 13 months compared to about eight months for physician choice chemotherapy.
00:12:31:20 - 00:12:55:23
Unknown
And so that's what you're seeing on the left. On the right is looking at survival like did patients live longer if they received the drug On the left, you're looking how long did it take for the cancer to progression on the right? You're looking at overall survival and the data are immature. They're not enough events to really report this out.
00:12:56:00 - 00:13:21:02
Unknown
We'll see how that trends in the future. But the one thing that I will say, and I just want to give this caveat is remember that this drug, tDCS, is already approved for her to low. And so there will be a quarter of patients who received chemotherapy and when their tumor had progressed, they could have gotten tDCS D as standard of care treatment.
00:13:21:02 - 00:13:47:20
Unknown
And that's going to dilute out the survival data that we see. But again, right now it's immature anyways. tDCS is a drug that we know, but I want to reiterate a few of the side effects that we see in blue are the side effects that we see from tDCS. And then like the grayish is what we see from physician chemotherapy.
00:13:47:22 - 00:14:15:16
Unknown
So the side effects that we see from tDCS are nausea, vomiting. I have some patients in my practice that they have no issues with nausea and vomiting, and then I have patients that need to come back to get fluids and intravenous anti-nausea medicines in order to support them on this. Well, about 50% of patients lose their hair. Not everybody loses their hair with this drug.
00:14:15:18 - 00:14:46:11
Unknown
The main side effect that it is important that we reiterate to patients is one, we monitor heart function every three months or so with ultrasounds of the heart. But the other thing that we see is about 10% of patients. There can be inflammation in the lungs. And if it gets to a certain extent where patients are actually coughing or short of breath, some patients need to stop the medicine and make permanently need to stop the medicine.
00:14:46:13 - 00:15:13:23
Unknown
So to reiterate what I showed patients who had her to low breast cancer, again, this was at the time that patients were transitioning from endocrine therapy to chemotherapy in the advanced setting. If they received DX There was a difference of about five months in terms of the median progression free survival for those that tDCS versus Physician choice chemotherapy.
00:15:14:03 - 00:15:43:01
Unknown
If it was HER2 low as well as if it was ultra low disease. And so you can see in blue the take home from this and that this study helps establish that this is an effective treatment option for patients with hormone receptor positive, HER2 negative HER2 low and then ultra low disease in metastatic disease in patients who at least had one prior line of endocrine therapy.
00:15:43:03 - 00:16:28:07
Unknown
These are slides that I'll show from Ian Krop, who is now at Yale, who discussed this study. And I agree with this Take them. So there's some things that I really like that I feel like are important to reiterate about this study. So one of the things for patients with hormone receptor positive HER2 negative or low or ultra low disease, we want to continue endocrine based treatment with or without targeted therapies like a CDK4 six inhibitor or like a3k inhibitor or like everolimus for as long as we can before we even need to think about chemotherapy.
00:16:28:07 - 00:16:58:20
Unknown
Right. And so the data that I showed you now show is after patients have received prior endocrine therapy because this is a marathon, this is not a sprint. And so we want patients to be on well-tolerated therapies which do not require time in the infusion center for as long as possible. So once a patient has a tumor that is no longer endocrine sensitive, that is when we start thinking about this drug.
00:16:58:22 - 00:17:26:13
Unknown
And I will say for some patients, when we start thinking about does somebody need chemotherapy or a drug like this is still reasonable to think about getting other drugs like Cytodyn, which is an oral chemotherapy to patients, especially patients who have limited disease. It may just involve the bone. It may be that they were on endocrine therapy for a long, long time.
00:17:26:15 - 00:17:53:16
Unknown
It's not inappropriate to think about giving kids vitamin for some patients, but if you have a patient whose tumor is rapidly progressing, they may you need may need a little bit more of a response and you're just concerned about the pace and the cadence of the disease. That's when I think, well, at least now I have D and I can give it a little bit earlier.
00:17:53:18 - 00:18:29:00
Unknown
So this is a schematic of where things are for metastatic endocrine positive disease, where we give endocrine therapy in a CDK4 six inhibitor, often front line. That second line is endocrine therapy with the three K inhibitor or maybe a continuing a CDK4 six inhibitor. And I'll discuss the data supporting that sort of approach in the next study or if a patient has an ESR one mutation, there are data about getting single agent illustrates.
00:18:29:02 - 00:18:58:03
Unknown
And so like I mentioned, you want to continue endocrine based treatments for as long as you can, but once you've reached the point where it's not responding to endocrine based treatments, that's when this study comes into context. So if a patient has her low or ultra low disease, it's reasonable to think about trastuzumab drugs taken though, for my patients who have a low volume of disease, like I mentioned, Capeside, I mean, it's absolutely reasonable.
00:18:58:05 - 00:19:26:09
Unknown
And then if a patient has truly HER2 zero two not ultralow but her to zero disease, then giving something like chemotherapy and then giving something like acid to ZMapp, which is a different antibody drug conjugate is entirely appropriate. The other thing that I will just mention is when I was sitting in the audience and I was listening to the data from the speakers as I was texting my pathologist just saying, Well, what are we going to do?
00:19:26:09 - 00:19:57:16
Unknown
Because at all of our institutions, we don't actually report ultralow. We reported, as were 2012, three positive low but we don't haven't been describing it as ultra low. So you may see at your specific institution that we're starting to evolve where once we have insights and guidelines that include ultralow, that we may be actually reporting this out in each institution maybe reported a little bit differently.
00:19:57:20 - 00:20:19:17
Unknown
But at Emory, where I am right now, we've already started to make that move so that we can try to get approval for patients who may have ultra low disease that would benefit from getting. All right. I look forward to any questions that people have about that study. And then I'm going to spend some time talking about post monarch.
00:20:19:19 - 00:20:47:09
Unknown
And then depending upon where we are, what time, I may actually stop and then see what questions everybody has because there's a good amount to talk about with this study as well. So this was a study that I was fortunate to present at ASCO, which is called the Post Monarch Study. So this study is again, we're talking hormone receptor positive her to negative disease.
00:20:47:09 - 00:21:12:17
Unknown
Though when I say negative, I mean anything but positive, right? So this could have been her 201 plus two plus just not positive. Okay. And so as a little bit of background and I've already kind of been alluding to hormone receptor positive metastatic disease, we've had some advances recently where we base decisions after a CDK4 six inhibitor. Right.
00:21:12:17 - 00:21:50:20
Unknown
So you have received endocrine therapy plus a CDK4 six inhibitor like palbociclib, ribociclib or MMR, cyclin. There are drugs now that are approved based upon the next generation sequencing that has been done either in blood or on tumor tissue. So for instance, if a patient has a3k or HRT mutation, we have the approval of a blessed. We also had the approval of copy of a certain and that's given often in combination with fulvestrant for patients who have an ESR one mutation.
00:21:50:22 - 00:22:23:15
Unknown
We have giving single agent illustrate right now and you can see in this schematic the median progression free survival is zero two for six months. These are the data from the studies in the biomarker positive population after a CDK4 six inhibitor. So in blue, these are the patients that got fulvestrant plus Aparicio, where you can see that the median time that they were on that combination was a little shy of six months for capacitive and fulvestrant.
00:22:23:17 - 00:22:52:17
Unknown
But that is compared to less than two months with single agent for Best Route, which is why we've moved away from giving single agent fulvestrant to patients and with an assessment the median progression free survival in the overall population. For those with ESR one mutations was about four months. And so you can see that while we have made some advances, we are looking for additional treatments to help support our patients after progression on a CDK4 six inhibitor and endocrine therapy.
00:22:52:19 - 00:23:31:21
Unknown
And also you can see the discontinuation rates that are observed in these trials where, you know, for Appleseed, for instance, about a quarter of patients had to stop the drug due to intolerance of of the drug. So this is the design of post ARC. And I will also say we've seen studies of giving if you've had endocrine therapy and a CDK4 six inhibitor and the tumor has progressed where you're randomized to switching the endocrine therapy with or without a CDK4 six inhibitor and we've seen some different results and these have all been phase two studies or about 100 or so patients.
00:23:31:23 - 00:24:01:00
Unknown
This is the first global Phase three randomized trial that is answering this specific question. So in this study, all patients had hormone receptor positive HER2 negative breast cancer. This is a true second line study, meaning that there were no other treatments that were given in the metastatic setting. After the tumor progressed. So none of these patients had chemotherapy in the advanced setting.
00:24:01:02 - 00:24:35:15
Unknown
Patients went directly from that CDK4 six inhibitor endocrine therapy to receiving fulvestrant with or without abemaciclib. Okay. And again, we were looking at how long did it take the cancer to progress. So there's some things that I want to point out. Two thirds of patients had cancer that was involved outside of the bone. 40% had disease in the liver or 20% had disease in the bone.
00:24:35:19 - 00:25:05:10
Unknown
Only almost all patients had received that prior CDK4 six inhibitor in the metastatic setting. You know, during the lifeline of this study about a cycle that was approved in the early stage setting, but it was less than a handful of patients that met those criteria. 60% of patients had prior palbociclib, a third had prior ribociclib and 8% had prior abemaciclib.
00:25:05:12 - 00:25:34:17
Unknown
A quarter of the patients were on that prior CDK4 six inhibitor for less than 12 months. The vast majority were on their prior CDK4 six inhibitor for greater than a year. And the only other thing that I wanted to point out is if you look at those who were on prior palbociclib or ribociclib in blue are the patients who were randomly assigned to the placebo arm and read or the patients randomly assigned to the abemaciclib arm.
00:25:34:19 - 00:26:18:20
Unknown
Numerically speaking, patients were on their prior palbociclib and ribociclib a little bit longer in the placebo arm compared to those that were randomly assigned to abemaciclib. So we talked about the Kaplan-meier curve and we these are the data that we have from this study. So you can see that the median time that patients were on abemaciclib plus fulvestrant, again, this is after a CDK4 six inhibitor was about six months in the fulvestrant alone arm.
00:26:19:01 - 00:26:48:18
Unknown
It was about five months. And this is the best that we have seen single Agent Fulvestrant do. There are a number of hypotheses of why this could be none of these patients had prior chemotherapy and all of the other studies they allowed prior chemotherapy in the advanced setting. Also, keep in mind that this study was going on at a time that we were seeing how patients with single agent for best were doing.
00:26:48:20 - 00:27:08:16
Unknown
And so we could have absolutely been biased in terms of the patients that we would have thought about putting on to this trial because of the concern that patients would have received single agent Fulvestrant So in other studies, the median time that patients are on single agent Fulvestrant is probably about four and a half months in other studies has been about two and a half months.
00:27:08:18 - 00:27:37:23
Unknown
So moral of the story is the placebo arm here did better than how we've seen in any of the other studies, both CDK4 six inhibition. But at the end of the day there was still a 27% reduction in developing progression. If patients were randomly assigned to abemaciclib. So I know that there's a lot that is on this slide, though it is an important slide.
00:27:38:00 - 00:28:00:24
Unknown
So we looked at different subgroups of patients and looked to see, okay, were there some patients who seemed to benefit more from being in the fulvestrant alone arm than those who were randomly assigned to abemaciclib Plus for best friend. So here this is the abemaciclib arm. You know, to the left and to the right is the placebo arm.
00:28:01:01 - 00:28:40:13
Unknown
And you can see all all patients pretty much seem to benefit from the addition of abemaciclib, you know, whether one had a disease that was measurable, whether one had disease that was in the liver. And we saw that the benefit seemed to be about the same no matter how long patients were on their prior CDK4 six inhibitor. The one real bit of conversation slash controversy that happened during the question and answer session during this presentation is that look at the bottom of this slide.
00:28:40:19 - 00:29:10:18
Unknown
In terms of prior CDK4 six inhibition, you can see that the hazard ratio that that curve that the where the red dot is that patients seem to do better getting abemaciclib if they had prior to palbociclib that benefit didn't seem to be quite the same if they had prior ribociclib. And there was a lot of controversy about this asking the question, you know, is the benefit here really being driven by prior palbociclib or not?
00:29:10:20 - 00:29:43:03
Unknown
But I just caution in terms of over interpretation of these data because, you know, almost two thirds of patients had prior habits like that. The ribociclib, relatively speaking, was small. And we'll see how this translates into future studies. It's too early to say whether this benefit is really limited to those who had prior palbociclib, because you can also see that that red dot for those who are prior abemaciclib was about the same as what we saw with prior palbociclib.
00:29:43:05 - 00:30:07:16
Unknown
So I'm showing you some additional kaplan-meier curves where you're looking at, well, how long was the patient on their prior CDK4 six inhibitor? Less than 12 months or greater than equal to 12 months. And you can see that both groups seemed to benefit. you know, there was a difference in both groups in those who were less than 12 months.
00:30:07:16 - 00:30:30:06
Unknown
The median time that patients were on the drug was about two and a half months longer. If they were randomly assigned to about a cyclist and about one and a half months, if they were on their prior CDK4 six inhibitor for greater than or equal to a year. And then the other thing that you're seeing here is whether patients pretty much had bone only disease or not.
00:30:30:08 - 00:31:00:24
Unknown
And if patients didn't did have bone only disease, there was about a 5 to 6 month benefit for those who were randomly assigned to abemaciclib, where you see the median progression free survival difference of 11 versus five and a half months in a patients had visceral metastasis rates of disease in the liver. The long that there was a benefit of about two months or so if you patients were randomly assigned to a a cycling.
00:31:01:01 - 00:31:23:10
Unknown
One other thing that we looked at you because I already talked about whether if you have a pediatric or active mutation, there's the benefit of giving a copy of a certain if patients have an S or one mutation, those are the patients that benefit from getting an assessment. So we looked at circulating tumor DNA. We looked at this in about 85% of patients.
00:31:23:12 - 00:31:53:10
Unknown
And what we saw was that regardless of whether a patient has an X or Y mutation or a3k mutation, that there's benefit for getting abemaciclib. And we will be reporting at upcoming Congresses additional data, looking at different mutations in the safety that we see from anti-oxidant toxicity that we see from abemaciclib as well known. The main side effects we see are gastrointestinal issues like diarrhea.
00:31:53:12 - 00:32:25:23
Unknown
In about 6% of patients needed to discontinue the drug due to toxicity. So the moral of this story from this study and then the next few slides, I'm just going to contextualize this and then I actually may start because I want to make sure that we have time to talk through any questions and clarifications that we need from the two studies, because these were really the two studies that I think caused the greatest amount of discussion at ASCO.
00:32:26:00 - 00:32:58:17
Unknown
So this was the first randomized controlled trial that looked at patients continuing a CDK4 six inhibitor and switching to endocrine therapy after their tumors had progressed on endocrine therapy, a CDK4 six inhibitor. And we saw an improvement in how long it took for breast cancer to progress. And we already talked about the rates of discontinuing the drug and that the toxicities are what we would have anticipated, primarily gastrointestinal issues.
00:32:58:18 - 00:33:41:12
Unknown
And so there seems to be a benefit of abemaciclib and fulvestrant, regardless, not selected for biomarker status, because I showed you the data that we saw this benefit regardless of patients who had an S or a mutation or three K mutation. So the take home from this study is that the addition of abemaciclib to fulvestrant improved progression free survival in patients who received a CDK4 six inhibitor in the first line, the patients who were on their prior CDK4 six inhibitor for more than a year and those who had primarily bone only disease were the ones who had the longest progression free survival.
00:33:41:14 - 00:34:07:14
Unknown
And so this is a potential option for patients, especially in patients who do not have a targetable mutation. So this was a slide that my colleague, Dr. Ruth R Ragan, who discussed the data which she presented. And I'm just going to spend some time going through this, and then I'm happy to open this up and answer questions that may exist.
00:34:07:16 - 00:34:38:08
Unknown
So patients, for the most part, are receiving endocrine therapy and the CDK4 six inhibitor front line, at least that's how things are at the moment. If a patient does next generation sequencing at that time and we're testing for any S one mutation or a3k, such a mutation, or if there are no mutations that are seen, which in post monarch was about 30% of the patients who are randomly assigned, we have options.
00:34:38:10 - 00:35:02:14
Unknown
The option is to either switch the endocrine therapy and switch the CDK4 six inhibitor. You can switch the endocrine therapy and use something like Everolimus. But if you've a patient who has a tumor that's rapidly progressing and you're just concerned that they're no longer endocrine sensitive, that's where chemotherapy may come in. That's where trastuzumab in the study we just talked about may come in.
00:35:02:16 - 00:35:26:18
Unknown
That's where sensitivity and critique in may come in. So that's where other non underpinned therapies may come in. So just to take a step back, if you have a patient who received an urgent therapy in a CDK4 six inhibitor and they have an actionable mutation, if they have a3k mutation, then you may think about giving them either a copy of Assertive or Appleseed.
00:35:26:18 - 00:35:55:00
Unknown
So I would say increasingly we're giving patients copy restricted because it's easier to tolerate than Uppal said. If patients have an AK T mutation, then copy this here to IS approved. If a patient has an ESR one mutation, then you may think about giving assessment. And then if patients have a tumor that have progressed on those, then you can go back and you can maybe give a CDK4 six inhibitor in therapy or maybe you can give Everolimus at that time.
00:35:55:05 - 00:36:18:18
Unknown
It really depends on the patient and what's going on in their disease at that time. The only other thing that I would say and then I will pause and I look forward to any questions that you may have, is that we know that capacity, given our policies, are not tolerated in all patients. As I mentioned at ASCO during the question and answer session, I practice in Georgia not.
00:36:18:18 - 00:36:58:13
Unknown
Everybody has uncontrolled diabetes. And one of the side effects, the major side effect that we can see from KP research have been alcoholism can be an increase in blood sugar and you actually need to go on. These studies have to have very strict criteria for your blood sugar control. And so if I had a patient in clinic who had a tumor that had progressed on endocrine therapy and a CDK4 six inhibitor and as a3k mutation but has an uncontrolled diabetic situation, I still may think about doing the data that we saw for post Monarch of giving fulvestrant plus abemaciclib, because I may be concerned about their tolerability of taking a copy of a sedative.
00:36:58:13 - 00:37:18:11
Unknown
And Apple said so at the end of the day, to me this is just adding one additional strategy for our patients. And the other thing that I will say, and I will pause for the questions that you may have, is that this is a moment in time. Like this is where we are right now in 2024. But the field is rapidly progressing.
00:37:18:11 - 00:37:44:00
Unknown
There are a number of new endocrine therapies that we will see readout from phase three trials in the next year. There are new CDK specific inhibitors. There, Newt specific three K inhibitors. There are other drugs that are optimizing are the benefit that we see from endocrine therapy. So this is where things are today, but the field continues to rapidly progress in a good way.
00:37:44:00 - 00:38:03:20
Unknown
Meaning, you know, we already see CDK4 six inhibitors have changed the landscape of how we treat patients. Assessed grades and assertive have been new additions to our armamentarium. And there's no reason to think that that will be the case for other studies that will be reading out for our our patients as well. So I want to thank you for your attention.
00:38:03:20 - 00:38:13:23
Unknown
I'm going to stop sharing my screen and I look forward to questions that you may have.
00:38:14:00 - 00:38:42:17
Unknown
Thank you so much, Dr. Chlumsky, for for that presentation on those two studies. That was a lot of information. So I appreciate you stopping and having some time for for some questions that specifically are focused on on those two studies. So we have a question and they really like to take a step back and talk about the age C testing and versus fish testing.
00:38:42:19 - 00:39:21:22
Unknown
And should patients be asking to be sure that both tests are done? Yeah. So I will even take a further step back. You know, when we when the first two test was being designed, it was really meant to be designed to distinguish positive versus negative. And now we are putting increased emphasis on a marker and a test that is being used in a way that it really wasn't initially designed.
00:39:21:22 - 00:40:03:19
Unknown
Right? It was really designed to just test positive versus negative. And so, you know, the marker itself can change over time. And so there are few points that I want to make. So one, if a patient has a tumor that is her to zero at the time of metastatic diagnosis, it is reasonable to re biopsy again in the future because there were some data, including data that were presented at ASCO last year by the Mass General Group, that the more biopsies you do, the more likely you're going to find something that's that's low.
00:40:03:21 - 00:40:33:12
Unknown
So that's point number one. And then, you know, point number two is just that our drugs are getting better. And, you know, there's what we call the bystander effect, where even if there's just like a little bit of HER2 that's there, we're able to get much more bang for our buck with drugs that are more active because it's, you know, impacting the local surrounding drugs cells.
00:40:33:14 - 00:40:59:06
Unknown
And so, you know, those are the points that I would make. But I also do think I do think that it's important that we still, you know, if you have a tumor that's 4 to 1 plus or two plus, it is absolutely standard of care to make sure that it's not just positive because that can. So you talked about we biopsy as you go on.
00:40:59:06 - 00:41:28:06
Unknown
Have you ever seen the case where someone may be positive and then they're like one plus and then upon progression, maybe years later, they actually change to zero. Could that come up? Is that and is that a problem? Because what we see with that data, it's talking you're talking about ultra low and zero. Yeah. You know, I think we're starting to understand this.
00:41:28:08 - 00:42:12:21
Unknown
The other thing to be clear is, you know, you have one may one may have different areas of cancer and we're only going in and biopsy in one area versus another. Right. So sometimes it's just based upon where you're sampling this do. And Dana-Farber presented some data in San Antonio this past December where they looked at that question, okay, well, if you had a HER2 two plus and then it was 4 to 0, and then at that point you got just using that direct stick in the take home point from their data was that the benefit from the drug seemed to be most dependent on what the last biopsy showed.
00:42:12:23 - 00:42:40:17
Unknown
Okay, So those are the data that we have now. But that was from, you know, a relatively small series of losses. Dr. Galinsky, I have a question that probably a lot of the audience is thinking, so I'm going to avoid what everybody else is thinking. So we listening to all of this are different ways of figuring out if you are her too low, her too ultra low or too negative.
00:42:40:19 - 00:43:05:15
Unknown
But in reality, every person has her two, right? It's not it's not something that there is very little, but every cell has a little bit of her too. So is there any reason at all? And I'm sure there is. And you would explain why we need to test for it at all because, you know. TRUDEL we use Trop to target and nobody tests for Trump.
00:43:05:15 - 00:43:35:01
Unknown
Two. So what is the point of going into all these detailed analysis of her to you know, of those patients have HER2 negative breast cancer, HER2 negative breast cancer, 85% of those have HER2 lower ultra low. There's a small proportion of patients who remain poor, 2000000. You know, but you're asking a good question and one that we ask.
00:43:35:03 - 00:44:01:23
Unknown
I mean, I've asked, so it's like, does it even matter? Right? Can you just give the drug that we may end up getting to that point and because we are a bit in a predicament now where we don't really report out her to low. And so now we're at a point where we have to convince payers to cover it and convince our pathologists to check in in the first place.
00:44:02:00 - 00:44:35:13
Unknown
And so, you know, as our drugs get better, I do think that that remains an important question for an imprecise marker. Thank you. That's that's good to know. So I want to ask you one more question related to HER2, and that is something that you actually had spoken about. The ILD, this rare condition that's very, very dangerous and it's evaluated by grade one, grade two and higher.
00:44:35:15 - 00:45:02:21
Unknown
So can you talk a little bit about when you would stop the treatment when a child is one or, will it be would you stop a do would you ever go back if a person has grade two or greater? ILD Yeah. So when the drug was first developed in the first early phase study, there were patients that died because of the pneumonitis, right?
00:45:02:22 - 00:45:44:10
Unknown
Because of the inflammation in the lungs. So even from its first presentation at ASCO now several years ago, that was the biggest concern in terms of the toxicity. So the way that the prescribing information defines what we should do is if one has grade one, which is asymptomatic and you just see it on the scans, then you should hold, you should give steroids, see that it gets better and then you can resume if it's grade two or higher meaning that patients have symptoms like cough, shortness of breath when supposed to give immunosuppression like steroids and then not be challenge.
00:45:44:12 - 00:46:12:12
Unknown
That's the book cancer. And it's very it's hard. This is hard. And I mean, I have a slew of patients who have I have two patients in particular right now in my practice as of this week, where this was an issue, one of whom is having a tremendous response to trastuzumab, directs T and probably has grade two pneumonitis, but also has disease where we need to do something.
00:46:12:14 - 00:46:39:00
Unknown
And so it's quite a clinical quandary. The book answer to your question is at grade two or higher, we should not be continuing grade one or lower like once it resolves grade one. If it resolves, you can re challenge. That's the book answer. We thank you very much, Kate. Yeah, So the next question I have is you talked a little about about about to dalvi.
00:46:39:02 - 00:47:05:14
Unknown
And so, you know, we have these two antibody drugs short dalvi and, and HER2 and they are approved already in the metastatic population. And then we have we're seeing some positive results with the Donald. Another antibody conjugate and think about asking your thoughts about sequencing of these drugs. If someone progresses on one, is it like are they likely to benefit from, from the other as well?
00:47:05:14 - 00:47:35:01
Unknown
Because they are they are similar but but yet different. Can you can I have your thoughts on that? Yeah. So the data that we saw at San Antonio last year were that the first antibody drug conjugate seems to be the one that patients benefit from the most, not always, but really most of the time. And that has been anecdotally what I have seen as well.
00:47:35:03 - 00:47:59:11
Unknown
Part of our issue at the moment in clinic is that while the target may be different, right, one is targeting HER2 and then the other two drugs that you just mentioned should be in data which isn't approved yet, but we hope we'll come to the market soon. Both target drug too, but the issue is, is that the chemo that they are linked to has the same mechanism of action.
00:47:59:11 - 00:48:27:17
Unknown
They're all to apply some inhibitors and so we are in need of newer targets with newer payloads, Right. Newer chemotherapies that they're linked to. And there are some that are very much in development, but that's part of the clinical quandary that we're in right now. And so to answer your question, I do sequence the ADCs. And the other question that they looked at is does it matter if you go directly from one ADC to another, you give something in between there, give a bit of a wash out.
00:48:27:17 - 00:49:03:11
Unknown
Does it seem to be better? Doesn't seem to have any difference. And so I often do back to back ADCs, but in general the first ADC is better in its efficacy data. I was going to go over to the next study and I was I have to tell you, I was completely blown away by some some data. And I want to ask you, but before I go to that, there is a question here live, and I think it's worth getting an answer.
00:49:03:13 - 00:49:40:17
Unknown
I think there is some confusion. So we're talking about hormone positive people who start their treatments in the metastatic setting with the current treatment. Once those once you become resistant to an agreed treatments, you start talking about later lines of treatment, right? You start talking about chemo in HER2. And by the way, that was a very interesting slide where you showed what to do for people either go to chemo or go to Enhertu or to Delta.
00:49:40:19 - 00:50:15:17
Unknown
But there is a question here Do we still need to stay on endocrine treatments once one, once we go to her to there seems to be some thinking that we might. Yeah. Yeah. So for patients who have estrogen receptor positive or to the low positive disease, ultra low, whatever the case may be in the metastatic setting, I often do not continue endocrine based treatments and the studies enhertu had a nice response right?
00:50:15:18 - 00:50:40:11
Unknown
We see really good shrinkage. And so I don't generally we don't generally think of the additional endocrine therapy is adding much besides possibly toxicities. And so often we were giving the antibody drug conjugate in the early in the metastatic set. In the metastatic setting, it is often giving them a lot. Thank you. Thank you very much team. You want to go to that?
00:50:40:13 - 00:51:14:12
Unknown
Yeah. So we have another question that's really important. I think we should target this one. So in progression, does it matter if you do a liquid biopsy or a needle biopsy? So liquid biopsies are easier for us to obtain, Right. And so when we are looking at the question of is something HER2 positive or too low or ultra low, that has to be done on the tumor, right?
00:51:14:14 - 00:51:42:24
Unknown
That's not done on a liquid biopsy that done on tumor tissue. And so if that's the question that you're looking for, you have to do a biopsy of it of metastatic site. Commonly we are doing outside of that the liquid biopsy. And then if that doesn't show anything, that's when I may do a biopsy to then do sequencing on the tumor.
00:51:43:03 - 00:52:12:10
Unknown
And maybe especially for these estrogen receptor positive breast tumors that have low volume of disease, have a low pace of disease, those are not shedding cells into the circulation months. And so that's the time that I reflect back and then do testing in the tumor, I think. Yeah. All right. So I'm going to go to on her because I'm really, really excited about that one.
00:52:12:12 - 00:52:57:19
Unknown
So One thing that completely blew me away was the slide where you showed the difference of progression free survival. Four Was it progression free survival of overall survival? I think for a group or all pillars on a BMI with visceral metastases versus the placebo control group. And the difference was just I guess, a month or so. So the question I have and probably people do too, is is it worth it in some cases to go all this additional And we know that the cycle is not an easy drug.
00:52:57:19 - 00:53:21:07
Unknown
There are a lot of side effects. Is it worth bearing a benefit to the regimen? Yeah. So we were looking at you're right, it was progression free survival and there was a difference of about two and a half months. And those who had visceral metastases about two months is about two months between those who had visceral metastases and receive fulvestrant versus post four plus abemaciclib.
00:53:21:09 - 00:53:52:08
Unknown
So I will say in other studies too, you know, whether it's the capital or 291 that led to the approval of Cohiba certain or solo one which led to the approval of a blessed visceral metastasis is just can be a more concerning feature. And so and the data that we showed here is is it is consistent what we've seen with the other studies.
00:53:52:10 - 00:54:25:03
Unknown
And I would just keep in mind that this is the median, right? This is the median time. There's some patients that are shorter. There's some patients that are longer in. So I think that those are patients in particular that we may have concern about the volume of their disease that I think is really the population who will most likely most benefits from combo therapy, but saying that the combo therapy that we're giving now could be better.
00:54:25:05 - 00:55:03:09
Unknown
Right? So that's the point that I was also trying to make in terms of where things are in 2024 is like these are the drugs that we have right now. We know the areas that we need to make improvements in. So this to me, this is laying like overall, overall in post monarch, even for all the patients who are getting abemaciclib plus fulvestrant, I think we can all agree we want better than six months media progression feature like we all want that right And so this is laying the groundwork for other studies and the benchmark that we're trying to surpass.
00:55:03:11 - 00:55:36:18
Unknown
And I'm hopeful with new drugs that are being tested that we could reach that. Okay. And I'll ask Keith. I'll ask a very good follow up question, because I think it's important also to mention that you you you noted it in the presentation that we talk a lot about now. Primary and secondary resistance. And primary resistance is a high risk group that progresses either while on adjuvant therapy or soon after.
00:55:36:20 - 00:56:08:11
Unknown
So we're not going to talk about in Evolve SIB, which is another new new drug that's quite promising. But you did mention in this trial in the Post Monarch study, there was a group that was tracked and that's that high risk group. So in your opinion, and did the trials show, is it worth it for that group once they progressed on the first CDK four, go to the next one?
00:56:08:15 - 00:56:32:23
Unknown
Yeah. For those patients who were on for less than a year, it was the minority of patients. That was the case is about 25% or so. They still seem to benefit in terms of the hazard ratio similarly. And those are patients that, you know, even if you look at Elsasser, it's for patients of S or where mutations don't seem to really benefit that much from an assessment.
00:56:32:23 - 00:56:56:00
Unknown
And so those are the patients that even feel more strongly giving a combo of drugs, understanding that I want that combo in the future to have greater activity can be. So I think we're running, we're running almost to the end. I think we're going to ask one quick question. I'm so sorry if we didn't get to your question.
00:56:56:00 - 00:57:21:08
Unknown
We have so many that we would love to answer. So we have a question. You had showed the sequence of treatment upon progression and looking at mutations. And we have a question regarding anything maybe new in the pipeline to replace the fulvestrant shot or have you heard of any of the oral steroids? And what does that look like?
00:57:21:08 - 00:57:48:14
Unknown
We know that there's a lot in clinical trials, and I'm going to point out two trials, one that's enrolling in, one that's completed enrollment to have your eyes. So the first this study that is currently enrolling is a study that's called the Lane Study, a Lane three study where patients had tumors that progressed on an urgent therapy, CDK four six.
00:57:48:16 - 00:58:27:12
Unknown
They have an S or one mutation and they're randomly assigned to fulvestrant plus abemaciclib, right. The post monarch combo versus these boxer boxes being, which is a new oral serum selective estrogen receptor modulator plus abemaciclib. So that's an ongoing study. And then the study that's been completed is ember three. So Ember three is a study of about 800 or so patients same kind of population where they're randomized randomly assigned to the oral third immune, desperate plus versus physician choice.
00:58:27:12 - 00:58:54:23
Unknown
Enter therapy like for best friends versus in the industry. Plus abemaciclib is that third arm that is going to be the most interesting of the arms because the question is going to be, well, how does that compare? You know, course, we don't want to do cross trial comparison, but what does that look like with that combo compared to what we saw with Fulvestrant Plus that that most likely it's a we're completely out of time.
00:58:55:00 - 00:59:26:19
Unknown
No time to ask. One more quick question. Dr.. We will have to have you back because you did not talk about triple negative. We did not talk about HER2 positive. I mean, there is so much stuff still to to go over, so you'll need to come back. That sounds good. Thank you so much. Please make sure to check out SHARE's upcoming educational programs and support groups and follow us on social media as well.
00:59:26:19 - 00:59:34:02
Unknown
This concludes the webinar. Thank you so much for coming by.