Introduction: Confronting Metastatic Breast Cancer (mBC)

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome to Improving Outcomes with First-Line Endocrine-Based Therapy for Patients with Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer. We have a great faculty today for this webinar, Professor Francois-Clement Bidard from the Institute Curie in the Versailles University in Paris and Dr Kevin Kalinsky from the Emory University School of Medicine, the Director of the Glenn Family Breast Center and the Winship Cancer Institute of Emory University in Atlanta, Georgia.

Today we’re here to talk about first-line therapy, specifically endocrine-based therapy, of patients with metastatic breast cancer, and particularly new trials that are trying to improve outcomes for these patients.

As always, we will be talking about the use of non-FDA-approved agents and regimens, so check out the package insert for more information.

Here’s where we’re heading today. We’re really going to focus our thoughts and attention today on 2 presentations, 1 from each of the faculty. Module 1, Kevin will do a presentation, and Module 2, Francois.

But we’re going to start out with a little bit of an introduction. I want to explain my garb here today and why I’m wearing what I am wearing. Maybe some of you who are football fans will know. But Francois, I know you’re maybe not so familiar with American football, but of course here in the United States that’s a big topic. And Saturday night was a very special night for us here in Miami, Florida, because the University of Miami, which I actually joined the faculty of, believe it or not, in 1977 with Dr. Chuck Vogel as my breast cancer mentor. I really focused on breast cancer when I went into really oncology underneath him.

And I’ve always followed the football team. I was watching the game Saturday night. And Francois, this is kind of like imagine you’re down 5 goals. They were down 25 points in the game. No way they could ever succeed, no way they could ever win, and yet they did. This guy, the guy who wore this, was their leader, and somehow, they managed to come away with a victory.

And it just made me think a little bit about facing impossible odds, which is of course sort of the beginning of the topic here tonight. When you think about first-line therapy in metastatic breast cancer, metastatic breast cancer in general, whether it’s ER-positive or not, usually we’re thinking about a situation that’s not curable.

But also it made me think a little bit, Kevin, about the fact, I was thinking about my mentor in breast cancer, Chuck Vogel, and he always told me, you know, there are these patients with ER-positive disease, sometimes others, where you can just kind of keep them going, maybe they’ll progress, but they may die of something else, 5, 10 years later. And actually, we actually started our company by producing a video called “Hormonal Therapy for the 1980s,” where we interviewed a bunch of women who were receiving — I don’t know if you’ve ever heard of aminoglutethimide, but one of them was getting that, fluoxymesterone, et cetera.

And I just wanted to start before we kind of dive into the fascinating data that you both are going to talk about trying to improve the outcomes of these women, of course we’ve come so far in understanding the mechanisms involved here, now we’re going to get deeply into that, just this idea of confronting the first-line — what we’re talking about here today, a patient and her physician confronting metastatic breast cancer in the first line, a situation that according to the textbooks, Kevin, is not curable, and yet somehow there are some people who manage to survive and maybe even die of something else.

Any comments on that experience? Any patients you’ve had that you think about in that regard as you maybe look toward a future with these new trials that’s really going to develop some other alternatives, what it’s like to take care of a patient who can survive so long with such a devastating situation, and what your thoughts are about maybe the biology, about why you see these extraordinary responders in breast cancer sometimes?

DR KALINSKY: Yeah, Neil. First of all, thank you for having us. I also feel like I would be remiss by not talking about the Vanderbilt/Alabama game, where also our pharmacist in clinic today like just came back. She’s an Alabama fan. I think she’s still like in a fetal position, so that’s another good example.

DR LOVE: Absolutely.

DR KALINSKY: I think that ultimately, we absolutely see some patients who are on front-line therapy for some time. I can think of examples in all the different disease subtypes that we see. These patients with hormone receptor-positive, HER2-negative disease who are on endocrine therapy and a CDK4/6 inhibitor. I have a patient who had just breast disease and then some metastatic lymph node disease who was on this eribulin/pembrolizumab trial and the subsequently stopped all of her therapy. And then same for HER2-positive disease, where we even saw in the CLEOPATRA study that there were patients who have HER2-positive disease, and even years out there’s a subgroup of patients who are still responding.

And I think the toughest conversation is (1) we’re excited and happy when we see this, and then there’s the question of okay, well can I stop. I understand that on my scans I may have microscopic — disease that’s just not being picked up, but do I really need to remain on this therapy? And that’s the kind of difficult situation where sometimes we say well, we don’t want to fix what’s not broken, but also, I don’t want to be overtreating you, and that’s where it gets tricky with these long-term responders. But we absolutely see it, and still to understand the biology remains an outstanding question in each of those subtypes, I would say.

DR LOVE: So Francois, another phenomenon that you see in breast cancer that, again, I just can’t comprehend, it’s been out there forever, is delayed recurrence. Why do you see somebody go 7, 8 years and then develop metastatic disease and die? Any thoughts about what it is that’s going on biologically in these patients who respond well? What’s going on in these people who relapse late?

PROF BIDARD: Yeah. That’s something that is kind of specific to breast cancer and mostly to HR-plus breast cancer, so this kind of super-long dormancy. So there is a lot of biology we don’t understand, and there’s a lot of explanation we cannot give to our patient because they will ask at some point why did I relapse, why is happening 20 years after I’ve been cured from my early breast cancer. So that’s something that is really not understood. Maybe it’s related to the immune system, immune system history, whether the immune system gets exhausted by something else. Honestly, we don’t know.

The good thing is that often these late recurrences have somehow good prognosis, so if you had, like, say, the age at initial diagnosis, and then you are 20 years for the late recurrence, and if you had the power and the long PFS we can achieve with our treatment. Let’s say these patients are more likely to die from something else than from breast cancer, and I think that’s our purpose and our goal as oncologists is to let’s say treat then for as long as we can and to maintain their quality of life. But hoping that’s — even if we cannot cure them maybe that they will get old enough to maybe die from something else, and I think that in that case we’ve done our job.

DR LOVE: Yeah. We just did a think tank on CML. We spent 3 hours talking about CML, and that’s always been our model for curing people, at least functionally.

Anyhow, let’s dive deeper into what we can do to make more patients live longer or maybe even get cured. This is kind of a summary of the current status of the use of hormonal therapy in the first and second line. We’ll get into a lot of these things.

But I’ve just got to ask one thing before we get started, Kevin. We asked the audience a question, that I was curious what your thoughts are, in terms of tolerability. Obviously, we’re going to get into how we can improve on what we have right now, Kevin.

But I’m curious how you see tolerability of CDK inhibitors right now. We did a program at ASCO where we showed a video of a doc in practice saying I give the older patients, 75, 80, 85, I give them the option of taking palbo because I think it’s better tolerated. And then I’ve talked to investigators who say well, ribo’s just as well tolerated as palbo, and of course it has a survival advantage.

We asked the audience what they thought about the tolerability of whether they thought ribo and palbo were equally tolerable, for example in an older patient. Just kind of curious, Kevin. You have an 80, 82-year-old patient, will you bring up — do you always turn to ribo, or do you bring up palbo? Would you bring it up in a younger patient? Do you think it’s better tolerated, better quality of life than ribo?

DR KALINSKY: I do. I do think it’s the easiest to tolerate of the CDK4/6 inhibitors, and if I had an 82-year-old patient I would and have discussed palbociclib as the front-line agent for those patients.

I would say in younger patients, especially premenopausal patients, but in general I would say ribociclib is my CDK4/6 inhibitor of choice. And I think that there’s some exceptions where there are drug/drug interactions that I’m worried about with giving ribociclib. I have seen significant liver function abnormalities with ribociclib. Abemaciclib, of course, the gastrointestinal issues.

The other thing that I will say is that there’s an ASCO-sponsored pragmatic study that is about to open. I think it’s called like the CDK Dosing Study, which is looking at older patients, meaning greater than or equal to 65, and then patients will either start at the standard dose or a lower dose and ramp up, ultimately seeing if there are any differences in terms of adherence and outcome.

DR LOVE: So curious about your thoughts on this, Francois. I was in Kevin’s camp. Actually, we polled the audience, and the most common answer is Kevin’s answer. However, the second-most common answer from the audience was actually palbo and ribo are about the same. And I was kind of shocked because I did a program with a very prominent investigator recently, and she said nah, I think ribo and palbo are about equal in terms of quality of life, et cetera. I see palbo being combined with stuff, including SERDs.

So what do you think, Francois? Do you think palbo has better quality of life or about the same as ribo, particularly in older people?

PROF BIDARD: Well, so to be honest, I think that for most patients it would be the same, but we are afraid by several stuff, especially in terms of comedications, EKG to be performed with ribo also. And also our staff to be also really has been used to using palbo and to see patients on palbo, and they know how to dose adjust and so on.

So I would say that it’s — I would call it a safer environment for an elderly patient to be put on palbo, because I know that everyone at my hospital, from the nurses to the residents, know to manage palbociclib and what to expect and what to look for. And that may not be fully the case with ribo in terms of co-medsin the elderly population. 

So I know that my oncogeriatrics at my site are really prescribing palbociclib most often. It’s not exclusive. And ribo could be well tolerated, but still we have kind of transaminitis and maybe slightly more concern about the safety there, even though there is no strong data to suggest — suggesting here is some difference in their ability. But because of the habits, and because palbo is apparently working, and because we don’t — what is the evidence of 5-year overall survival in an elderly patient population, that has a lot of comedication, comorbidities and so on? What we just want is to stabilize the disease for the next couple of years, so palbo is probably doing a good job in that.

DR LOVE: One of our themes in almost every program we do is getting the patient involved, if they want to, and certainly in situations like this if a patient wants to have a voice they certainly, I think, should.

Mechanisms of Resistance to Endocrine Therapy in HR-Positive mBC; Use of Oral Selective Estrogen Receptor Degraders (SERDs) — Dr Kalinsky

DR LOVE: Alright. Let’s dive a little bit into the data. I was noticing that your director of the Glenn Family Breast Center, Kevin, actually started, I think, the first breast center for indigent people in the United States at the University of Miami that still exists, University of Miami Jackson Memorial Hospital, really a great opportunity here in Dade County.

But let’s go through the data looking at the issue of how — the mechanisms of resistance that we see in hormonal therapy and where SERDs fit in. Kevin?

DR LOVE: Great. Alright. So we’ve recognized that endocrine resistance can be associated with a worse prognosis in hormone receptor-positive disease, and so what I’m showing you in this slide is that these are patient-level data. These are from 4 randomized clinical trials, and you can see just the median overall survival comparing those that have endocrine-resistant disease compared to those who have endocrine-sensitive disease.

And as per the conversation that we were really just having, in terms of the CDK4/6 inhibitor trials, we have approval for 3 CDK4/6 inhibitors, palbociclib, ribociclib and abemaciclib, where we see a progression-free survival hazard ratio that is similar across the trials, but overall survival some differences. Also recognizing that not all of the studies were powered to look at overall survival.

So when we think about how tumors behave after CDK4/6 inhibition it’s important for us to think about some of the resistance mechanisms that can exist. And these are some data from the MSK group, where looking at tumors before and after CDK4/6 inhibitor you can see an increased rate of ESR1 mutations, which is an adaptive resistance mechanism that we’ll be spending a lot of this hour talking about, and also the development of, for instance, RB1 truncating mutations.

So ESR1 mutations essentially make those agents that we have, like aromatase inhibitors, not effective, and we think about agents such as selective estrogen receptor down-regulators and some novel endocrine therapies being mechanisms or ways for us to overcome this resistance. I imagine that Francois will also talk a bit about this, but when we think about the prevalence of ESR1 mutations, for patients when they’re starting their — before they start their first-line endocrine therapy in the metastatic setting, that rate of ESR1 mutations is about 5%. But then, after front-line therapy, when we look in the second and third line, it’s somewhere between 30% to 40% of patients have ESR1 mutations.

And we’ve seen historical data where, and this is what really drove the — helped drive the clinical utility of checking for ESR1 mutation, so of course the approval of elacestrant also drove this, as well, where we saw that patients in the SoFEA and EFECT trial, if they were randomly assigned to exemestane, and they had an ESR1 mutation, they did not really seem to respond, as opposed to the patients who received fulvestrant, who even if they have ESR1 mutations may respond to single-agent fulvestrant.

So if we look at the different trials that we have, this is just a table that’s looking at various targeted therapies in various settings, again just to really make the point that ESR1 mutations front line, before patients start their endocrine therapy in the first-line setting is low, about 5% or less, but once you start getting post-CDK4/6 inhibition that starts to increase.

This is a slide that is just highlighting the fact that not all ESR1 mutations, hotspot mutations, are the same. And there are some data that for instance those with Y537S mutations, these are some in vivo activity, that fulvestrant may not be as active as what we see with some of the other ESR1 mutations. And it’s just really asking the question at some point if we have additional SERDs approved will we get to a setting where okay, you have a D538G mutation, would you think about giving this SERD, if you have a Y537S mutation this, or even the question of whether we’ll be seeing oral SERDs having beneficial activity regardless of the presence of ESR1 mutations, including those who are ESR1 wild type.

So I just spent some time talking about SERDs, but there are other novel endocrine therapies for us to be thinking about. There are additional SERMs that are in development, like for instance lasofoxifene. There are complete estrogen receptor antagonists like palazestrant, there are PROTACs such as the ARV agent, and then there are SERCAs as well.

But the only approved oral SERD at this time is elacestrant, and this is also a study that Francois knows very well, which is a study, the EMERALD trial, which essentially looked at patients who had tumors that had progressed on or after first or second-line endocrine therapy, one of which was given in combination with a CDK4/6 inhibitor. Patients were allowed to have at least 1 line of chemotherapy, and patients were randomly assigned to single-agent fulvestrant versus investigator choice standard of care therapy, including fulvestrant. And there were dual primary endpoints, where they looked at progression-free survival in all patients, as well as those who were ESR1 mutants.

And it is worth noting that in terms of progression-free survival that this was based upon blinded independent central review. That was the primary endpoint.

So these are some data that I actually think are clinically relevant that were recently reported in Clinical Cancer Research, which looked at how long were patients on their prior CDK4/6 inhibitor, really looking at this as a surrogate of endocrine sensitivity. And you can see that for those patients who were on their prior CDK4/6 inhibitor for at least 12 months that’s when we start to see a real delta in terms of the benefit of elacestrant, where in this particular case it’s a median PFS of 8 months compared to about 2 months for standard of care hormonal therapy and a hazard ratio of 0.4.

SERDs are being evaluated in various settings. They’re being evaluated in the metastatic setting. They’re being evaluated in the operable setting. I’m only highlighting here 1 study, which is the pionERA study, which is looking at this endocrine-resistant population, so for patients who have tumors that progressed on or quickly, within 12 months or so, after completing their adjuvant endocrine therapy, which is looking at giving fulvestrant/CDK4/6 inhibitor versus giredestrant/CDK4/6 inhibitor.

DR LOVE: So before you go on, Kevin, just a couple of questions. First to come back to Francois and thinking a little bit about this last slide that you went through showing the other SERDs that are in development. One of the things that I’ve been hearing, Francois, is that some of these have SERM-like qualities, elacestrant in particular I’ve heard that, as opposed to being a pure SERD. Is that true, and, like, what does it mean? Is it an advantage to have a pure compound? And at this point, with indirect comparisons, can you differentiate anything in terms of efficacy with these agents?

PROF BIDARD: Well, that’s a good question. Yeah. So I think that’s a practical level, like in vitro level. There is some stimulation of the estrogen receptors that could be achieved by some of these compounds, so let’s say a more SERM-like compound, so more a modulator than an educator. And elacestrant is one of them at the in vitro level. But in the clinic, does it matter? We don’t know exactly at the moment, because there are no side effects, let’s say at the uterine level or even at the bone level.

So we don’t know really if it matters in our patients. It could matter in terms of side effects because the 2 agents that are most known to be let’s say pure SERDs, which are camizestrant and giredestrant, have kind of common side effects, lower heartbeat and also some vision blurry — blurred vision. So it could be that those are kind of class effects between the pure SERDs versus the SERM SERD, but in terms of side effects or in terms of toxicity I don’t see much of a difference. So not very relevant for me in the clinic.

DR LOVE: So Kevin, I’m curious also in terms of some of the strategies, and Francois is going to talk a little bit about this. But one of these agents, camizestrant, we’re going to talk about the Phase III study, but first of all was looked at in the SERENA-2 Phase II study compared to fulvestrant. One of the things that I noticed at is as we started to treat people with fulvestrant after CDK it looked like they weren’t getting as much benefit as before CDK, but in any event, maybe that had something — I’ve heard maybe that has to do with the dose, et cetera. Any thoughts about what we learned, though, from the SERENA-2 study, Kevin?

DR KALINSKY: Yeah. From SERENA-2 I think we (1) saw that — and it was a smattering, as you mentioned, where some patients had prior CDK4/6 inhibition, others did not. I think we saw that there was some activity with camizestrant, and it was really a proof of principle that we should be evaluating this in a larger trial.

I also think that it’s important to note that the time of response post CDK4/6 is less, right, and that is something that we’ve seen with other Phase III randomized trials. And so when interpreting these data it’s just important to note that there is kind of a mixed population, so if you look at those patients who didn’t get prior CDK4/6 inhibition they seemed to do better in both of the arms.

DR LOVE: So I’m curious also, Francois, and again, here’s some more data that we were talking about. You were just mentioning prior CDK versus — again, versus no prior CDK. It looked like without prior CDK — with prior CDK they had a greater hazard rate there, also looking at whether they benefitted by ESR1, and it looks like most of the benefit seems to be in ESR1 patients. Do you agree with that, Francois?

PROF BIDARD: Yeah, yeah, fully agree. So let’s say that’s something that we have seen with many agents. We have seen it with elacestrant in EMERALD, and we are seeing it now with camizestrant in SERENA-2. So this data is showing that the new agents, such as camizestrant, are more active than the old agent fulvestrant, in patients with ESR1 mutations. And apparently in patients without ESR1 mutations they are equally active than fulvestrant. So overall if you mix together the 2 populations the new drugs or the old drugs, next-generation SERDs, are more active, but could be slightly more active, but if you divide by ESR1 status then you have stronger activity in the ESR1-mutated subgroup, yes.

DR LOVE: We’re going to talk about a fascinating trial. Actually, I discussed this trial, not this one here, but well actually this one and the one we’re going to talk about looking at people who flipped to ESR1 while they’re getting therapy. Investigators outside of breast cancer are very fascinated.

But I’m just kind of curious, Kevin. This is the SERENA-4 Phase III ongoing study, first-line therapy in metastatic disease. Pretty straightforward. Again, palbo being the CDK that it’s combined with, but either cami or anastrozole. I’m just kind of curious, what do you think we’re going to see quality of life-wise or interruption of therapy-wise, Kevin?

DR KALINSKY: My guess would be that it will favor those patients who received cami. I think Francois had mentioned this, with cami we can see that photopsia, right, where patients feel like sometimes, they have a little bit of a blurry vision, but that goes away. I mean, as we know, with the aromatase inhibitors there’s a notable — sizable population that have toxicity like arthralgias, et cetera. And it’s nice to have potential agents that don’t cause this because adherence can be challenging, especially in the early-stage setting. And so we’ll see how it looks in a randomized Phase III trial, but I think ultimately quality of life will be better.

DR LOVE: So I’m going to let you go back to your presentation and pick up with this slide here from the ASCO Rapid Recommendation. I remember, we had Hal Burstein, who was I think in charge of this, at one of our meetings, I think at ASCO. And he was telling us what a headache it was to try to figure this whole thing out, go through all the data, and that hormonal therapy was getting too complicated to do guidelines on anymore.

But anyhow, they did come up with some pretty important practical recommendations, Kevin. Can you continue?

DR KALINSKY: Yeah, for sure. And ASCO, after their approval of agents, like they’re doing these Rapid Recommendations related to —

DR LOVE: Right.

DR KALINSKY: — to help establish these guidelines. And so I just wanted to highlight the point that it is recommended that for patients with hormone receptor-positive, HER2-negative disease that have tumors that have progressed on endocrine therapy with or without a CDK4/6 inhibitor that we are doing ESR1 mutation testing. And part of the debate that we had within the committee was how to frame the conversation about the kind of testing that we should be doing, and ultimately we landed on that one should be doing blood-based ctDNA just given that it’s — there’s greater sensitivity, but that if you’re seeing wild-type, or you’re not detecting anything, that it may be worth collecting tumor and then seeing whether you can identify mutations.

This may seem just a little bit off topic, but I felt like it was important for us to mention INAVO120 is a study that’s looking in this endocrine-resistant population. So I’m going to shift gears for just a moment because I’m really talking about patients, again, hormone receptor-positive, HER2-negative disease that have PI3K mutations. And this is a patient population similar to what I was describing for pionERA, but again, this is just for patients with PI3K mutations, where patients had measurable disease and then they were randomly assigned, Neil, as you had mentioned, to fulvestrant/palbo versus the triplet of fulvestrant/palbo plus inavolisib, which is given once a day. It’s a PI3K inhibitor. It’s not yet approved, though I suspect it will be coming to a clinic near us soon.

And the reason I really brought this up is look at the median PFS that we see for patients who are getting doublet therapy of palbo plus fulvestrant, right, it’s about 7 months, compared to the triplet, where it’s about 15 months, and the hazard ratio is 0.43. And we’ve seen updated data. We’re waiting for the paper to be published, but I do think that this will be clinically impactful for those patients who have PI3K mutations with endocrine-resistant disease.

And so really my general take home is that we have novel endocrine therapies, we have our oral — the first oral SERD, elacestrant, but I really suspect that these agents and other novel endocrine therapies will continue to have an important role in hormone receptor-positive metastatic disease, as well as potentially in early-stage disease as well.

DR LOVE: So Kevin, you had a case, kind of a typical case, but I think a good one just to bring up to kind of get in front of us in terms of where we are right now with the typical use of a SERD. Maybe you can just present what happened with this 42-year-old woman.

DR KALINSKY: For sure. So this is a 42-year-old woman, had right invasive ductal carcinoma, Grade 2, hormone receptor-positive, strongly hormone receptor-positive, “HER2-low.” She had not had prior breast imaging. It was T3N2. She had staging scans, which showed bone and lung mets. She had a lung biopsy confirm metastatic disease. She was having some back pain. Excellent performance status. Does not have a hereditary mutation. And the patient underwent a TAH/BSO.

As I had already kind of alluded to, based upon the MONALEESA-7 data, she sent on to get an AI and ribociclib. She was on this for around 3 years or so. She had a tumor that had progressed. She had a ctDNA that was checked. She had an ESR1 mutation, Y537S.

And these are things that when we see patients that we consider for them, whether — well, (1) she does not have an alteration in the PI3K pathway, so agents like alpelisib or capivasertib are not one that we would think about, whether we should give her an ADC like trastuzumab deruxtecan based upon the DESTINY-Breast06 data that we have seen, or other chemotherapy or ADCs, or whether we should remain with endocrine therapy, such as giving elacestrant. And also, we have data about switching the endocrine therapy backbone and continuing the CDK4/6 inhibitor plus the MAINTAIN — per the MAINTAIN or postMONARCH data. So we have several options. It’s just a question of how we should be best sequencing these options.

DR LOVE: So I think people probably wouldn’t be surprised if this lady ended up on elacestrant, is doing well.

Incidentally, any tolerability issues she’s had?

DR KALINSKY: No. I mean, I will say my experience in clinic, this agent is well tolerated.

DR LOVE: So Francois, we actually found out that we’re presenting 3 posters at San Antonio, and 1 of them is a survey we did of not only investigators but also elite general medical oncologists, and one of the most — about how they manage second-line hormonal therapy. And one of the most interesting things we found is what happens if you take this same case and had a PIK3 mutation. And I was really curious what the investigators were going to say and what the docs in practice were going to say. I’m going to tell you what we’re going to report in our — it should be embargoed or something, but anyhow.

I’ll tell you what we saw in our survey, but I’m just kind of curious, how do you handle these double-mutated patients?

PROF BIDARD: Well, I’m going to hide behind my French environment, which we don’t have access to alpelisib in France currently, and also, we’re looking forward to getting access to capivasertib. So at the moment it would be fulvestrant plus everolimus, or we could consider elacestrant as a single agent. So depending on the first line, here the first line was long enough to consider elacestrant single agent, that would be my choice.

And if I were in the US my experience with alpelisib is not so good. So with long PFS in first line I would still believe in ESR1 or at least go for elacestrant or a SERD, fulvestrant or one of the new SERDs, maybe in combination with something else, like everolimus. And fulvestrant/alpelisib could be good because it’s targeting both ESR1 and PIK3CA, but still the toxicity of alpelisib, for me, is a concern.

DR LOVE: So again, assuming all available options, which sort of are in the United States, Kevin, how do you think through this situation? Do you always go with the same or do you tailor it to the situation? How do you approach it? A lot of people say well, elacestrant’s going to be better tolerated, but how do you approach it?

DR KALINSKY: Yeah. I mean, I actually — when I answer this question I think about when I was a trainee and my attending would say, “Oh, like it really depends on the situation.” I thought, well, that’s not really — like, that’s not an answer. But that’s actually what I would do. Where if I had a patient who had indolent, slow-growing bone mets I feel like elacestrant is absolutely appropriate.

If I have a patient who I’m really concerned about the cadence, like the — well, we would have known that the cadence was relatively so, but if now the patient has significant visceral disease or something where I feel like I need a little bit more activity than something that’s single agent, I think as Francois had mentioned, fulvestrant/capivasertib, fulvestrant/everolimus is a good option. And also the other option is something like fulvestrant plus abemaciclib per the postMONARCH, particularly if I’m concerned about somebody who may not be able to tolerate getting capivasertib, somebody who has uncontrolled diabetes for instance.

DR LOVE: So it’s like when we do these surveys we always learn from the surveys, and then we have to change it for the next time. But what we saw here, because we just asked people what they did, it was like 50/50, investigators — and we didn’t realize that you’ve got to like shade it in terms of the situation. And actually also the general medical oncologists, same thing, 50/50. So as you said, really a lot of flexibility in this situation, as there often is in breast cancer.

Ongoing Evaluation of Early Therapeutic Switching for HR-Positive mBC Harboring ESR1 Mutations — Prof Bidard

DR LOVE: Alright. Let’s move on now and really start to get into some of the strategies that we’re looking at to improve long-term outcomes, particularly this fascinating strategy. Again, I talk about these — this trial in particular using cami in this situation for people who develop ESR1 mutations to investigators in other tumor types just as an example of looking at resistance early, and they’re fascinated by it. So you guys are like in the lead, from what I can tell, in oncology in looking at this.

But Francois, we asked you to explore what’s behind all this.

PROF BIDARD: Yes, thank you. So it’s always a pleasure, and I think that breast cancer has led like most of innovation in oncology, so it’s very good for us to continue with that. So here it’s about a new strategy, which is to —definitely to target ESR1 mutation as soon as it appears. So it’s really important to understand the kinetics and when this mutation appears in the course of the disease and how to target that.

So I start with, just for context, the first line. So we are very happy with our current first line with either palbociclib, ribociclib, abemaciclib, and we discussed how to choose between the 2. But here the question is really how to extend this first line, and the issue is first line if you look at the curve, is that none of these curves has a plateau, which means all patients will eventually progress, and with this disease progression, we know that afterwards there is shortened, and we touched on this also, shortened PFS in second line.

So this is an example with fulvestrant. Fulvestrant, remember, it was 11 months in SOLAR in patients that were not pretreated with CDK4/6 but in BYLieve with patients that were CDK4/6 pretreated. The median PFS on alpelisib was just cut by half, so that’s — let’s say, once a patient is progressing on CDK4/6 inhibitors, it’s very important to keep in mind that the next line is much shorter.

So these are other examples of the current PFS we are getting with — so with a contemporary trial with the first CDK4/6 setting, elacestrant 3.8 months, fulvestrant plus abemaciclib 6 months, and fulvestrant/capivasertib 7.3 months.

I think these median PFS are fine, but they are not very satisfactory. The patients had like 24 months or even longer PFS in first line, and then they will deal with very short PFS in second line. So again, we need to do a bit better. We need to increase time on the first line because when the patient progresses on CDK4/6 then we are facing a lot of trouble. So we need to understand the acquired resistance mechanisms to CDK4/6 inhibitors plus AI to understand really how these resistances are happening and how to tackle this resistance.

When it comes to resistance to CDK4/6 inhibitor, so we have it in combination in first line, we have the AI, and we have CDK4/6 inhibitors.

We don’t know much about the resistance mechanism, but the ones we know are rare, and we cannot target them. So we could let’s say forget about these resistance mechanisms for the moment, but we could focus on something that is very important, which are these ESR1 mutations. And as shown on the screen here, these resistance mutations are appearing during the first line.

So again, if you look at the first line, so before starting the first line, less than 5% of patients display an ESR1 mutation, and when there is disease progression on the AI given at the metastatic stage, up to 40% of patients have an ESR1 mutation detected. So these mutations are appearing in between during the first line.

And what is interesting is that if you detect an ESR1 mutation that is rising and appearing in the blood, at that time the tumor may still be sensitive to CDK4/6 inhibition. It is only a resistance that is happening, that is developing and resistant to the AI partner, to the endocrine therapy partner, but the CDK4/6 inhibitor may still be efficient. So the idea is to use a drug that could be — that could target ESR1, and endocrine therapy, and we have one, which is fulvestrant, and we know, and Kevin has shown that we have data showing that fulvestrant is efficient in ESR1-mutant patients even though the PFS that is displayed here with plasmaMatch and EMERALD. As you see, fulvestrant is not a very efficient drug, not a very potent drug, in patients when it’s given after disease progression.

With that in mind, so we have these rising ESR1 mutations that are appearing during the first line, and what we have done in PADA-1, so it’s an academic proof-of-concept trial, so that was run in France. So with about 1,000 patients. These patients went on AI plus palbociclib as first-line treatment, and we monitored in these 1 thousand patients, the appearance of ESR1 mutations.

So at the very beginning very few patients had an ESR1 mutation, but we knew we would intercept and would detect these rising ESR1 mutations in the blood. And patients with detected rising ESR1 mutation in the blood without disease progression were then randomized — they have a molecular signal of resistance to AI, so we randomized them between the usual strategy, which is not to take into account the signal, so patients continued the same treatment, or we just did a small switch, which is switching the endocrine therapy partner from AI, apparently not working anymore, to fulvestrant, which is known to be more active on ESR1 mutations. So it’s a small change in the endocrine therapy partner, but we are targeting the resistance mechanism to the endocrine therapy while maintaining the CDK4/6 inhibition.

So again, the idea was to delay disease progression and also kind of optimal use of SERDs as a targeted therapy against ESR1 mutations, and the question was is it feasible to — is it acceptable by patients. In terms of results — we showed it is feasible, and it is well accepted by patients, but in terms of results what we got is that with the most recent PFS data we got a delta between the 2 arms of more than — about 7 months, which is much longer than what you can get with fulvestrant used after disease progression. So I think this kind of delta really draws the attention to PADA-1 because it is suggestive of a benefit of using fulvestrant as soon as ESR1 mutation appears in the blood.

We had also like kind of carryover effect, I’d say, in terms of PFS2, time to second tumor progression, from randomization with a clear benefit in favor of the switch to fulvestrant.

In terms of safety, the beauty of this strategy is that it’s just a small switch. Patients are maintained on their CDK4/6 inhibitor, so we had no toxicity — with no significant toxicity, just a switch from the oral drug, AI, to an intramuscularly delivered drug, fulvestrant. So nothing much happened to our randomized patients, and so we had very good benefit in front of this, very little toxicity profile.

DR LOVE: So just to quickly go to Kevin. Any thoughts about this strategy and how — and what you’ve heard up to this point in the talk and what your thoughts are about it?

DR KALINSKY: Yeah. I mean, I believe I’ve said this directly to Francois, but I will say this publicly. Like I think that this was a study that we’ll look back and say was the study before its time, right, because I think that this is a — it’s a study and a strategy that could really make sense. I think that, as Francois knows, I think a lot of people are waiting for the results of SERENA-6 to really help confirm in a larger study with a newer SERD whether we’re seeing the same effect for PFS and then ultimately also for PFS2. But I do think that Francois got ahead of the curve by doing this. I have a strong — if I were a betting person, I would say that we will see this benefit in SERENA-6.

DR LOVE: I like that kind of estimation there. So this is the SERENA-6 Phase III trial. This may be how we’re going to be treating breast cancer in the near future, but can you talk a little bit about the background in terms of how this was put together and the specific design, Francois?

PROF BIDARD: Yeah, sure. So SERENA-6 — again, PADA-1 was an academic proof of concept trial. It was a small trial done in France. Here, SERENA-6, it’s really like the next level. First, it’s a global Phase III trial. It is registrational, and it is registrational for camizestrant. And camizestrant, as we discussed earlier on, is more active than fulvestrant on ESR1 mutation, so we expect a signal of activity that could maybe exceed the signal of activity we’ve seen in PADA-1. So it’s a very promising drug when it comes to targeting ESR1 and like really an interesting strategy.

So what is done in SERENA-6 is the same idea of PADA-1, is like screening and monitoring the appearance of ESR1 mutation while patients are being treated with AI and any CDK4/6, so palbociclib or abema or ribo. These patients could enter SERENA-6, get the ctDNA screening, that was done every 3 months in SERENA-6, and in the case of a rising ESR1 mutation, exactly the same course utilized in PADA-1. Then patients were randomized again between staying on the same treatment, and we don’t pay attention to the biomarker, or we switch the endocrine therapy to camizestrant, which is a very potent drug, and the CDK4/6 inhibitor partner was maintained, so unchanged, same dose, same drug. So it’s really like a switch of the endocrine therapy when you see an AI is not working anymore.

So in terms of enrollment, so the study has been — enrollment has been completed, and what is interesting is that we will have the readout probably in 2025. And the potential benefit we may document — we have maybe touched on with PADA-1, but that we document with SERENA-6 here like really maximizing the SERD efficacy, and we expect to really show that the benefit is higher, or it’s really strong with a switch when you see this mutation popping up in the blood. And why is that? It could be, like — it could be related to the fact that early targeting — targeting resistant subclones when they are still a minority in the tumor, could be a more efficient strategy. And again, the idea is to maximize. We are seeing these patients developing resistance to the endocrine therapy partner, so we can keep these patients on CDK4/6, and we could maximize the length of the first line, so getting more months and more time to our patients.

DR LOVE: So we’re going to go on in a second and have Francois present this case, as we’ve got a lot of questions for Kevin to address. But I’m just kind of curious. We’re getting a lot of people asking questions in the chat room about how often in the trial they check for ESR1 mutations, Kevin. But I’m just kind of curious, do you see any rationale for a doc right now in practice to look for this? Would that make them more suspicious of an early recurrence? Or any reason, any rationale for somebody to be looking at it before we see the data?

DR KALINSKY: No. I don’t think so. Not until we see SERENA-6. I mean, I think that there’s a lot of interest just in terms of — really, we utilize ctDNA now for the detection of mutations. Like this is asking about the development and monitoring for the detection of mutations, and I think that we will get there, but I think it will depend upon the results of SERENA-6. And Francois alluded to this, and I agree. This was a — PADA-1 was a smaller study. The confirmatory study is SERENA-6.

DR LOVE: And again, one other question, Kevin. What are we looking for in order to make a change in practice? PFS? Survival? What are you thinking?

DR KALINSKY: How much time do we have left? I think that the primary endpoint is PFS, and I believe, and Francois, correct me if I’m wrong, but the collection is every 3 months just looking for ESR1 mutations. And so this study, I suspect, will read out once we see PFS. I do think that there will continue to be an interest in terms of PFS2, and then we’ll see if there’s an overall survival advantage.

And Francois, correct me if I’m wrong, I’m not sure that the study’s powered to look at overall survival. Please correct me if I’m wrong. But I do think that the community will be very interested in knowing what PFS2 will look like, and just to make sure we’re on the same page, that’s the time from randomization to the time of the second progression.

PROF BIDARD: Yes. You are right.

DR LOVE: So we actually have a cool case. We have a cool case in the chat room from Kathleen. I hope we can get to it, a 73-year-old woman with a 15-year history of stable oligometastatic disease who now sounds like she’s progressing.

But let’s go with Francois’s case first, a 69-year-old lady. What happened with her?

PROF BIDARD: Yeah. So for the sake of time I’m going to just like recap what is on the slide. So basically a patient with de novo breast cancer, ER-positive, put on letrozole and ribociclib. So treatment is well tolerated, and the patient is coming back to your clinic, like it’s an interactive case. So the patient is coming back to your clinic after 3 months on treatment, and she’s tolerating well letro and ribo.

So at that time I imagine you’re also reviewing the results of tests that you have ordered. Somatic NGS testing showing BRCA — no BRCA mutation in germline but PIK3CA mutation in the breast tumor, and there was no ESR1 mutation detected.

The first question, which is very easy, is should we expect to find an ESR1 mutation in the tumor tissue. Again, the biopsy was performed prior to treatment start. And also in terms of comutation between PIK3CA and ESR1, that kind of comutation, and what happens when the patients has a germline BRCA2 mutation, does it impact the onset of ESR1.

So I’m providing some of the answers. The first question was related to do you expect to find an ESR1 mutation in the tumor tissue. The answer is clearly no. And as we already discussed, it is very important, again, to keep in mind these mutations appear after exposure or during exposure to an aromatase inhibitor given for metastatic breast cancer.

And we have data in PADA-1, and we looked prior to treatment start, so prior to AI and palbociclib. We described the factors associated with a higher prevalence of ESR1, so we are able to detect ESR1 in about 3% of patients. We have factors that are associated with a statistically increased incidence of ESR1. But if you look at the numbers, like even 7.1%, the maximal incidence we saw in a defined subgroup, so overall ESR1 mutations are very rare prior to treatment start and prior to AI exposure in metastatic — in the metastatic state.

When it comes to other data outside PADA-1, so this is a study that — reporting data from FMI, so NGS done mostly in the US, and you see both — you could detect ESR1 on tissue and also on blood, and the percentages displayed at the bottom on the slide are increasing alongside with line of treatment. So again, we are seeing this mutation really emerging during treatment with AI, so the more you test the more you detect, both in tissue and in blood, but of course blood is much easier to do when it comes to repeated assessments.

When it comes to PIK3CA mutation, so there is no significant mutual exclusion or association, so overall 15-20% of patients are expected to have at some point both a PIK3CA mutation, which is present from the beginning of the tumor, and an acquired ESR1 mutation, so nothing to expect much here.

BRCA, for the last part of the question. If you have a patient that has a BRCA2 mutation in a metastatic ER-positive breast cancer, what do you expect on AI plus CDK4/6? It has been documented by the MSKCC team, but also, we found — we are confirming it in PADA-1, that these patients have a shorter PFS on AI plus CDK4/6. But when it comes to ESR1 mutations, the rate of ESR1 mutation is pretty similar in these patients, so the presence of BRCA2 mutation does not prevent the onset of ESR1 mutation.

So then the question about — remember, so the patient is coming back at your clinic at 3 months, and you are telling the patient about the risk of ESR1 mutation appearing during therapy. And here Kevin, maybe I’ll ask you about what are the main talking points when you are — what would you do. I understand you are not doing it now in your clinic, but what would you do if you had to — you wanted to discuss about — explaining ESR1 and what is — why you need to test, and what is the purpose of it, and what is the meaning of it.

DR KALINSKY: Yeah. Yeah. I mean, I think the biggest question is whether intervening early is going to make a difference, right, because we know that the tumor’s not going to be as responsive to an aromatase inhibitor-based therapy while patients are developing ESR1 mutations. And so I think the clinical quandary, like in real life, I think the clinical quandary would be you check an ESR1 mutation while you’re on an AI and CDK4/6 inhibitor, you see an ESR1 mutation, you do scans, you don’t see progression, what do you do. And that’s where we — the data we have now would suggest switching to fulvestrant-based treatment. But again, it would be nice to have this in a larger study and the question about a novel SERD instead of fulvestrant.

DR LOVE: So we’ve kind of ran out of our time here. If you want to check out more of the case, in the chat room we have the slides there for you to take a look at, including several slides here at the end with some new trials and new datasets in the adjuvant, as well as the neoadjuvant setting. Also PROTAC studies.

But there are a couple questions in the chat room I just want to run by Kevin really quick. Sohail brings up the issue of a patient who has an ER of 10%. I’m going to ask you, is that — what about 5%? Is that ER-positive or not? And does the PR affect it? A pretty basic question. She actually says 10%, PR 40%. Is that ER-positive?

DR KALINSKY: Yeah. I mean technically, based upon ASCO-CAP Guidelines, and we know that if you have positivity for ER and PR, PR can be an indicator of endocrine therapy response.

I tend to worry when I see a patient have low estrogen receptor expression given endocrine-based therapy in the metastatic setting. However, I have also seen second opinions where they come to me, and their provider had done such an approach, and patients have had a response. And so it still makes me worried, given some of my own anecdotal experience, but the truth is I’ve seen otherwise too.

And I think the question is also like when was that biopsy. Was that biopsy done in a time that was close to when we were treating?

DR LOVE: I mean, you’ve heard of HER2-low, but I think we ought to be talking more — a lot more about ER-low. I’m not sure. Do you give them — if they have localized disease do you give them KEYNOTE-522?

So final question back to you, Francois, again from the chat room. Danny wants to know whether you have any concern for lead time bias confounding the PFS assessment with PADA-1 or SERENA-6.

PROF BIDARD: Yeah. So lead time. It refers to a lot of notions. Most of the time we understand lead time as early diagnosis of metastatic relapse. Here it’s not the case. Like patients are already on their treatment, so it’s just a switch from one to another.

And the magnitude we’ve seen with fulvestrant, with adding fulvestrant, showing a delta of 6 months, is suggesting there’s a real delta between the 2 arms. It’s suggesting in fact that it’s much stronger than is seen later on. I have shown you that later on fulvestrant single agent or even combined with CDK4/6 gives you like 2 months or 3 months, which is much shorter than the 6-7 months we’ve seen in PADA-1.

So that’s currently all the data we have. We’ll see again. So that’s maybe not enough to convince. Again, I understand PADA-1 was kind of…We’ll see what happens with much more potent drug with camizestrant in SERENA-6. So we need to build more data to convince that it’s a switch of therapy for the patient, but it’s also a switch of management for the doctor, so of course we need to provide some strong evidence.

DR LOVE: So I want to thank the faculty for working with us today. Thank the audience for attending. Be safe, stay well and have a great night.

Thanks so much, Francois. Thanks, Kevin. Have a good one.

DR KALINSKY: Thank you.

PROF BIDARD: Thank you.