Unlocking the Impact of ESR1 Mutations and PI3K Pathway on Elacestrant in Advanced Breast Cancer

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale. Shepard, a Medical Oncologist here at Cleveland Clinic directing International Programs for the Cancer Institute and Co-Director of the Cleveland Clinic Sarcoma Program.

Today, I'm happy to be joined by Dr. Azka Ali, a Medical Oncologist here at Cleveland Clinic specializing in breast cancer. She's here today to talk to us about the impact of ESR1 mutations in the PI3-Kinase pathway on elacestrant in patients with advanced breast cancer. So, welcome.

Azka Ali, MD: Thank you for having me, Dale.

Dale Shepard, MD, PhD: Give us a little bit of an idea of what you do here at Cleveland Clinic.

Azka Ali, MD: Yeah, so I'm a medical oncologist in the breast group and I see patients, men and women with breast cancer. And in terms of my research, I'm interested in looking at areas of resistance development in metastatic breast cancer patients, and ultimately with a goal to identify novel targets.

Dale Shepard, MD, PhD: All right, excellent. Well, we're going to talk a little bit about some research, and this is some research that was discussed at the San Antonio Breast Cancer Symposium, specifically about ESR1 mutations, management of patients with hormone receptor positive HER2-negative breast cancer. So give us a little bit of an idea of the research you guys presented there.

Azka Ali, MD: Yeah, so hormone receptor breast cancer that's HR positive, HER2-negative. This continues to be a very exciting and complex at the same time space. Exciting because now more than ever in the last few years, we have lots of targets that we have identified and lots of treatment that we have developed, but also remains complicated because now the ongoing questions are how do we sequence these treatments and what comes first, what comes after?

So in this study that we presented at San Antonio Breast, we looked at real world outcomes of patients that were treated after elacestrant was FDA approved. And it's important to go back to the real world data because when we have trials we can really control those patients. They can be sometimes very different than our real patients than you and I see in clinic. So it is important to go back to the real world data because I think it's probably closest to the clinic.

Dale Shepard, MD, PhD: We may have people listening in a bunch of different backgrounds. Let's take a step back. When you say real world data, what does that mean? How do we get it? How does that compare to trial data?

Azka Ali, MD: So there's multiple ways to get it. Real world we typically call retrospective. I think real world just sounds a little better now, but essentially we could do it individual query on our data bank here at Cleveland Clinic. We do a lot of those here. This in particular was a combined effort with Guardant Inform platform where Guardant kind of led this effort to look back and identify patients that had all these mutations that they had picked up through their assay and then we were able to get additional information on those patients. So definitely this could be done on an individual cancer center level, clinics level or with a big multi-effort, which could be multiple platforms.

Dale Shepard, MD, PhD: So essentially this is patients who weren't on the trial that led to approval, but patients who've gotten it since then?

Azka Ali, MD: Correct.

Dale Shepard, MD, PhD: What kind of happens?

Azka Ali, MD: Exactly. So these are patients that get it after the drug has been FDA approved and patients that you and I treat in clinic. And again, I think it's more important to see the real world data because a lot of times these patients are going to be more heavily pretreated than we allowed on the clinical trial. Sometimes even older, sometimes even performance status not as robust as we typically have in our clinical trials, but again, those are patients that we are seeing in clinic every day.

Dale Shepard, MD, PhD: Now one thing that was interesting that you just mentioned was that this was actually something that was in collaboration with a testing company because this is a particular drug that there's a mutation involved and we'll talk about that. But oftentimes these real world studies are from a company that may have done a trial and they're like, "Okay, now what really happens with our drug?" So how did that come about in terms of working with a testing company?

Azka Ali, MD: So obviously we work quite a lot with our testing company, our laboratory partners, and I think we mutually help each other because we obviously need their assays and obviously these are great assays, we're using them every day. Also, it's a pool to look at a lot of data that's there to be mined. So I think these collaborations are extremely important, whether they are at the academia level or at the community level because there's a lot of data out there that we're collecting from our patients. If we don't go and look to see what's happening, it's just sitting there and we can learn a lot and we can really use that information to perhaps make our treatments better and more effective.

Dale Shepard, MD, PhD: And outside of having to do a really expensive time-consuming prospective trial.

Azka Ali, MD: Yeah, absolutely.

Dale Shepard, MD, PhD: All right, so this particular study, what kinds of data did you draw in and what did that study look like?

Azka Ali, MD: Yeah, so elacestrant as you mentioned, is an oral agent. It's a selective estrogen receptor degrader. It is different than some of our endocrine therapies that we have like Tamoxifen, which is a selective estrogen receptor modulator or aromatase inhibitors, which block the kind of peripheral conversions of androgens to estrogens. These are different because ESR1 mutations... Perhaps I should take a step back and tell you what those are. There are different types of mutations that can develop, particularly with hormone receptor positive HER2-negative breast cancer. ESR1 mutations are mutations that develop over the lifetime of breast cancer. So these in a de novo metastatic patient or a patient that has had perhaps adjuvant or post-op therapy, estrogen blocker therapy, they maybe are present at less than 5% incidence, but patients that are metastatic on endocrine therapy, particularly aromatase inhibitors, these can be as high as up to 50%.

So these essentially develop over time. So this also has changed our treatment schema a little bit because we weren't really doing serial liquid biopsies or serial tumor biopsies on our patients, but when we have this type of information that we learn now, it is imperative for us to go back and do serial liquid biopsies to pick up these mutations and offer new agents to our patients.

ESR1 mutation is a mutation in the ligand binding domain of the estrogen receptor. So the ligand binding domain kind of changes and it is rendered almost like permanently active even in absence of the ligand, which of course is the estrogen. So the selective estrogen receptor degrader or elacestrant in this scenario will go and degrade that the sort of terminally turned on receptor. So this drug is very interesting. It's also orally bioavailable. So it's really exciting that we have yet again an oral therapy because right now in our first line we're using a lot of oral therapies and those are typically our endocrine partners, aromatase inhibitors, often given with our biologic CDK-4/6 inhibitors.

There is, I think to make matters a little more complicated, there's another mutation pathway PI3K which you mentioned. Those mutations are a little different from ESR1 mutations because those are truncal or mutations that are present at the beginning of cancer development. So we can track those back as early as the initial biopsy or the breast cancer surgery, or you can pick them up at a metastatic site biopsy or even liquid biopsy, and those mutations can be as frequent as 40%. Now what we have learned in the last few years that PI3K, the downstream of that, it turns on AKT and then there's one other protein that kind of down regulates the AKT, which is P-10. We have also learned that there could be alterations in the AKT about 5% and in P-10 about 5%. So we have now three agents of now approved that target that pathway.

So we had alpelisib, which was a PI3-Kinase inhibitor. Then we have the PI3K AKT P-10 alteration pathway inhibitor capivasertib, which was approved last year. And as of last month we have inavolisib approved, which is approved in a very specific situation, but it's a PI3-Kinase inhibitor. So I guess the question would be how do we put everything in context of how do we treat our patients? Because as we can appreciate that this landscape has gotten really, really complicated.

I think one question that continues to be ongoing is how do we sequence the PI3K mutation inhibitors, pathway inhibitors I guess versus ESR1 mutations. So what we have attempted to do with this study is to look at some of the real world outcomes of our patients, maybe get some insight into sequencing, insight into type of ESR1 mutations because we're learning that story might be more complicated because the type of ESR1 mutation may matter, and some of those mutations may confer more resistance to endocrine therapy.

And what we have attempted to do is kind of break down those additional points. I will also add that elacestrant was approved off of Phase 3 EMERALD study, and I think again, kind of going back to why real-world data is so important in that study, really well-designed study because it allowed a hundred percent of prior CDK4/6 inhibitor use, which is fantastic, that represents a very real-world population.

They also allowed prior fulvestrant, actually 30% of patients had prior fulvestrant. Once again, very real-world, a lot of our patients are going to have fulvestrant. And then they also even allowed prior chemotherapy, although only 20 to 22% had prior chemotherapy. Most of them were chemo-naive patients, and those that did have chemotherapy, they had only one line of chemotherapy. When you look at the data that we presented at San Antonio Breast, you'll see that over 50% of these patients were chemotherapy-treated patients because the question would be that these are estrogen-blocker endocrine therapies, perhaps we should use them up front. If your patient's already in chemotherapy, perhaps we're not going to get any benefit from these. But I think this study gives me a lot of encouragement as an oncologist that I can go back and target that mutation and I might be able to get some response from those patients.

Dale Shepard, MD, PhD: You mentioned that it's important to think about the specific mutation. What were sort of your findings? Did you end up finding that some of the mutations there was better benefit from this drug than others?

Azka Ali, MD: Yeah, that's a great point. So there are several ESR1 mutations. Majority of them are mutations in the ligand-binding domain. There are some ESR1 fusions, which probably are not as sensitive to the SERDs or selective estrogen receptor degraders. The most common mutations are D538G, and Y537S. It looks like Y537S is the one with the highest transactivation activity and greatest resistance to tamoxifen, fulvestrant and some of the other SERDs.

Our kind of hypothesis was that perhaps when we break it down by mutations, we might see a different pattern in terms of patient outcomes. We found that 70% of our patients had D538G mutations, and 51% had Y537 mutations. So again, kind of consistent with what we were expecting to see, what we have seen in the literature, but interestingly, having the mutation did not really predict any better or worse outcomes. Now that once again this is one data set, it is a over 700 patient data set, so it's a good number of patients. I think it tells us that there's a lot more work to be done and it's very important to build these type of exploratory endpoints when we design these studies because sometimes we get a lot of signals in preclinical and we may or may not replicate that signal in our studies.

Dale Shepard, MD, PhD: So there wasn't a difference based on the specific mutations, but how about the number of mutations?

Azka Ali, MD: Yeah, so in terms of number of mutations, we did see that if patients had four or more ESR1 mutations, those tend to do a little worse in terms of their outcomes versus those that had up to three mutations, which again could suggest that there's some sort of a polyclinality with these mutations that's conferring this inherent resistance to ESR1 pathway blockade.

Dale Shepard, MD, PhD: And then I guess when you mentioned that there's things like the separate PI3K pathway, what was your finding in regard to people that had that not only the ESR1 mutation, but also a PI3K mutation?

Azka Ali, MD: So there is some early work and some interesting work by some of our colleagues. So Naomi Dempsey has actually done quite a bit of work out of Miami in the co-mutation space. Her group had a very interesting abstract at ASCO where they looked at a total of over 600 patients. So the incidence of co-mutations, ESR1 and PI3K mutation at the same time is about 10 to 15%. And in her work, they also found that the incidence of co-mutations was about 10 to 15%. They saw that and they were again looking to kind of answer questions on sequencing. If you've got both mutations, what do you use first is the ultimate question.

And they saw that patients that had both mutations, it was probably better to use the PI-K3 inhibitor first. Although a lot of the elacestrant-treated patients that data remain immature, a lot of those patients were still on treatment because the drug has only been approved for less than two years, and a lot of those patients were pending actually their radiological evaluation. So we don't really have a lot of data. I think there's more to come on that.

What we saw in our short follow-up real world analysis is that having a PI3-Kinase co-mutation is likely associated with a negative prognostic impact on elacestrant itself. Now we're not really able to draw conclusions. What's better to do, right? What's better to do first? I'll tell you what I do. I tend to do the PI3K target first. Although I think we don't really know for sure what the right answer is.

Dale Shepard, MD, PhD: Is that because you start off with the PI3K mutation and then you are acquiring the ESR1s, and so by doing it afterward you sort of acquired things and then use that drug? Or is that kind what drives that thought?

Azka Ali, MD: Yeah, so I would say a part of it is the mechanism of how these mutations develop. I think part of it is that we think PI3K pathway, which again kind of leads to AKT downstream mTOR, we've utilized mTOR inhibitors in this space knowing how the pathway works. We think it's a very important pathway in endocrine resistance. So if we have a patient that's having progression and that mutation is there, I think one theory is that that pathway could be very largely driving that resistance to the first-line endocrine therapy, perhaps second-line endocrine therapy with like fulvestrant, but still with a CDK4/6 inhibitor or fulvestrant monotherapy alone.

So I tend to target that mutation first, although I think it should be noted that toxicity of these treatments is really real and important to realize. PI3K treatments, right now we're giving them as a partner with an endocrine partner. So those are usually after patients have had aromatase inhibitors, NA CDK4/6 biologic in the upfront setting, and we have come down to PI3K inhibitor. We are typically given that within intramuscular agent, which is fulvestrant, which means that your patient that have been on oral therapy is now going to require clinic visits.

The other I think, important aspect of this whole situation is that toxicity of PI3K inhibitors is still quite a bit. It's manageable, but they do have quite a bit of toxicity. So for example, hyperglycemia, we see them with all of them. It is a on target, but undesirable effect, many patients end up going to metformin or some sort of another anti-hyperglycemic agent. So that can be an issue if your patients have diabetes already, that could be an issue or diabetes that's not well controlled.

When you kind of pivot to elacestrant, it's an oral agent largely really well-tolerated. So if I have a patient where toxicity has been a big issue, especially in the upfront setting, even in presence of both mutations typically go to the elacestrant option in those patients because once again, while we have some interesting preclinical signals, we have some interesting patterns from real world data, we don't really know if one is truly preferred than the other.

Dale Shepard, MD, PhD: When we think about that real world versus trial comparison, as I recall in the data that you generated, the progression-free survival was longer in the real-world data than what was seen in the trial. And then you'd mentioned a lot in the real world data actually more people had had chemo and so maybe even additional lines of therapy, but still did better from a PFS standpoint. So what do you think drives that? Was that surprising?

Azka Ali, MD: Yeah, it is surprising, I'll be honest. Especially when we look at the number of patients. I think 40 over 40% had chemotherapy. Many of them had antibody drug conjugates. Actually 15% of the chemo treated patients had antibody drug conjugates. So it's actually over 50% of patients that had chemotherapy. So while it is surprising, I think it also tells us that this treatment schema is still very complicated and we still, there's a lot that we don't understand, particularly in terms of what ESR1 mutations are and how an individual ESR1 mutation drives resistance and responds to therapy.

I would also say, I think in real world, sometimes we may be a little more permissive of maybe a mild slow progression that may or may not be meeting resist criteria that might be just a bone only progression, but our patients are doing well, pain is not really worse, and we're trying to avoid chemotherapy for as long as possible. I think sometimes there's that sort of a bias as well from an investigator or a clinician rather standpoint. Again, I think there's a lot that we need to go back and look into the EMERALD data and our real-world data, but very surprising as you mentioned.

Dale Shepard, MD, PhD: Yeah. So from a very, very practical standpoint, how do you go about, what's your approach to monitoring patients with testing, doing the ctDNA tests?

Azka Ali, MD: Yeah.

Dale Shepard, MD, PhD: At what points in your current practice are you testing? Where are you testing? When are you testing? How do you test?

Azka Ali, MD: Yeah, so I would tell you every three months when I get asked this question every three months, I have a different answer.

Dale Shepard, MD, PhD: Well, we'll have you back.

Azka Ali, MD: Yeah, exactly. Part of that is because as we get more data, as we get more drug approvals, as we get more Novel ways to measure these biomarkers of resistance, we're constantly changing our treatment schema. So if you had asked me that three months ago, I probably would've told you that I'm not doing upfront next-generation sequencing on tumor or liquid. I'm usually doing it at that first progression beyond CDK4/6 inhibitor to look at, find the ESR1 mutations that are dynamic in rising in blood.

The PI 3K mutations if they are there again, you will get that same information from liquid biopsy or a tumor genomic assay if that's what you choose to do. The third PI 3K kinase that I mentioned that was just approved inavolisib, that is approved in a very special situation in patients that have either progressed on adjuvant endocrine therapy or those that have completed their adjuvant endocrine therapy in under 12 months, which means that those patients that have had a metastatic recurrence, either on adjuvant therapy or those that were on adjuvant therapy as of the last 12 months, they can now go on to get fulvestrant with a CDK4/6 inhibitor. In this study, it was palbociclib with the novel PI three kinase inhibitor inavolisib.

So now we're looking at a triplet combination up front versus the doublet that we have talked about. So in that setting with that approval, and we saw again, a near doubling of PFS in these patients, and of course we are interested in that patient population because there is something inherently resistant in those patients, and if we can double that PFS, that's fantastic. Now the question is, well, what happens after? Are we just doubling the PFS up front and then the patients get less and less time on subsequent treatments? And that's a question that's yet to be answered. But with that recent approval of inavolisib, now I am actually doing NGS or ctDNA up front to find that PI 3K mutation, and when I do identify it, I am looking to incorporate inavolisib in my treatment schema.

Dale Shepard, MD, PhD: This is certainly getting more and more complex. So we've gone from treat breast cancer to hormonal status to HER2 status, and now mutations and breast cancer is becoming quite honestly a series of rare diseases with unique sort of-

Azka Ali, MD: It really is. It really is.

Dale Shepard, MD, PhD: Phenotypes and genotypes.

Azka Ali, MD: Yeah. And what I find myself is I think it's complex enough for two oncologists talking about it. When I have some of these discussions with patients, they're obviously getting increasingly complex. So sometimes I would actually refer them to patient-type resources that are either vetted by a medical group or if it's an outreach program that the clinic is conducting. I think it's very important for patients to understand why these discussions are so complicated. I think they've been used to just being told what's the right therapy for them, and they just kind of figure out how to take it. But it is important to tell them, "Hey, these are the treatment choices. This is why we are making these choices and what toxicity is to be expected."

Dale Shepard, MD, PhD: I was just talking to a couple of colleagues, our regional colleagues recently, they have a really hard job. They see a wide range of tumors. This sort of information like we're talking about, is it getting out into the community in terms of their decision-making, the sort of assessing mutational status and things like that?

Azka Ali, MD: That's a good question, and I think that's where it kind of comes back to partnering with our industry partners. So whether that's a partner that makes an assay or whether that's a partner that is geared towards education in the community, particularly medical education. So I do quite a bit of that, whether it's education alone, whether that's updates of recent work, whether that's presentation of the work that I'm doing.

I also, I would say on a very kind of local practical level, have a lots of colleagues in the area that I'm utilizing them when I have a patient that needs to go on an IV treatment and I need them to deliver that local care. So we have that kind of bidirectional relationship where if they've got a complex situation, they just kind of pick up the phone and call me and we just have a chat about it. So I think whether we are practicing in the community or academia, I think knowing who you send your patients to or knowing who you refer your patients to when you have questions, I think that type of dialogue is getting more and more important.

Dale Shepard, MD, PhD: Well, certainly interesting work you've developed. It's a growing field, and I look forward to hearing about your new testing strategy in the future.

Azka Ali, MD: Absolutely. Absolutely.

Dale Shepard, MD, PhD: So thanks for being with us.

Azka Ali, MD: You're welcome. It's been a pleasure.

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