When should endocrine therapy change in HR-positive metastatic breast cancer, and what evidence should guide that decision?
SABCS Co-Director Virginia G. Kaklamani, MD, joins Erika Hamilton, MD, of Sarah Cannon Research Institute, and Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center, to discuss the SERENA-4 findings alongside SERENA-6 and what they mean for treatment decisions.
Video Transcript
Virginia Kaklamani, MD [0:00:03]: Hello, everybody. My name is Virginia Kaklamani, one of the co-directors of the San Antonio Breast Cancer Symposium, and I want to welcome everybody to this edition of SABCS Snippets.
Today, we’re going to talk about the evolving landscape of HR-positive metastatic breast cancer in the context of the most recent press release from SERENA-4, and I want to welcome two distinguished guests, Dr. Erika Hamilton and Dr. Komal Jhaveri — both of them really being PIs of pivotal trials that have led to FDA approvals of drugs in this space. So, really excited to have both of you here today.
Komal Jhaveri, MD [0:00:39]: Thank you so much for having us. It’s always fun to discuss the SABCS Snippets new data. So, looking forward to our discussion today.
Erika Hamilton, MD [0:00:46]: Happy to join you guys.
Dr. Kaklamani [0:00:47]: So, let’s start with a case. We have a patient that was diagnosed with de novo metastatic disease, HR-positive. She’s starting therapy with a CDK4/6 inhibitor and an aromatase inhibitor. Erika, walk me through what you would do in that setting in this patient.
Dr. Hamilton [0:01:03]: Yeah, so, absolutely. I think you’ve definitely clearly outlined our first-line standard here: endocrine therapy with a CDK4/6 inhibitor. And it’s been big recent news for ER-positive breast cancer. We do have approval of SERENA-6 now, and as you recall, this was kind of 1.5 line, or ctDNA monitoring in the first line.
And so really looking at those patients that are on first-line AI and CDK4/6 and monitoring ctDNA for the emergence of an ESR1 mutation. If patients have an emergence of an ESR1 mutation, then we’re kind of looking to see if they actually have progression. And in the absence of progression, that study looked at either remaining on your endocrine therapy with that CDK or switching to the oral SERD camizestrant and continuing on the same CDK4/6 inhibitor.
The progression-free survival with the switch strategy was improved by 7.6 months, and a lot of people were kind of asking the question of, “Well, what would have happened if patients had just been allowed to stay on that therapy and then ultimately gotten the oral SERD at the time of progression?” They did try to answer some of those questions by looking at progression-free survival 2, which was also improved with camizestrant in the switch strategy. That was 6.6 months improvement.
And so we recently did hear that this is now FDA approved. And so in this trial, the ctDNA monitoring was every two to three months, so kind of to correspond to when we would be doing imaging or scans in these patients. So I think monitoring for ESR1 is now a possibility for us in the first-line space, and really thinking about switching treatment for patients before we might see actual progression on scans.
Dr. Kaklamani [0:02:56]: So Komal, most of us are now using ribociclib in the first line as the CDK of choice, and there’s some concern about the QTc prolongation as well as bradycardia. That is something that happens with ribociclib and camizestrant. How would you address that if you had a patient on ribo, but then you were thinking of using the SERENA-6 approach?
Dr. Jhaveri [0:03:19]: What a practical question, Virginia, and something really, really relevant in our clinic, given our practice currently to utilize ribociclib predominantly. So, I think it’s a very relevant question.
So, the accelerated approval for SERENA-6 that we were just discussing is with any CDK4/6 inhibitor, which is the good news. When we look at the details of the population that were studied in the SERENA-6 trial, they were predominantly palbociclib, which again makes sense for the timing of when this trial was designed and what our practice patterns were then, right? So we were using predominantly palbociclib back then when the trial was designed and conducted, and our practices to switch to ribo changed much later. But that population on SERENA-6, obviously, is not very high — you don’t have a very big proportion of patients who did receive camizestrant and ribociclib, at least in that particular study.
And when you look at the guidance that the accelerated approval provides, they do remind us that yes, the safety profile is great. Yes, the toxicity of these oral SERDs as a class in general has been well tolerated and is low grade, and that’s true even for camizestrant. But we still have to remember a few things that happen very distinct with each agent, and we know that there is some photopsia or visual disturbances that we’ve seen with camizestrant — low grade, transient, but yet something to remember when we have to tell our patients and educate them about that.
And the second one is bradycardia, and potentially being careful when patients are on multiple drugs that could have interactions and cause QT prolongations. And we know that’s a distinct side effect with ribociclib as well. So now we have ribociclib, where we do EKG monitoring. We have the FDA guidance of what we need to do when we start a patient on ribociclib, with three EKGs that we do two weeks apart, and then we have a similar kind of guidance that has also been provided with this accelerated approval.
And I think we have to remember that, because these patients are already on ribo, which means we finish the EKG monitoring back when we started them, and then eventually when we switch over and continue the ribo and just add the camizestrant, I think we might want to remember and take a look at the medications patients are taking. We might want to probably do the EKG monitoring that they are asking us to do, and also think about the electrolyte values which might be relevant for QTc prolongation. So I think those are the kind of things that practically we might have to remember, given our current practice patterns and given what we know about these drugs.
I would just add that at least what we have learned is that we don’t see a whole lot of grade 3, but at the same time we want to be vigilant and make sure that that’s true in the real world, because that was a trial setting where we are really very vigilant. And I think when we’re trying to adapt this into practice, we don’t want to lose sight of that.
Dr. Kaklamani [0:06:08]: And as you mentioned, only 15% of the patients on SERENA-6 were on ribociclib, so we have to be a little careful and cautious, and remind our providers to do those EKGs.
Erika, we soon are likely going to have combination therapy approvals with our oral SERDs — potentially the EMBER-3 approach with the combination with abemaciclib, and also the evERA approach with the combination with everolimus. So, how will you look at those approvals in your clinic and make a decision as to whether you should switch early or whether you should wait at disease progression and give a combination therapy?
Dr. Hamilton [0:06:45]: Yeah, I think that’s a great question, and we don’t have all of that data really to compare, right? We really just have these individual trials in silos right now. I think the magnitude of benefit — 7.6 months — is compelling. There is some quality of life data that’s still kind of maturing from SERENA-6 as well: a suggestion that particularly bone pain was improved. And could that be kind of prevention of progression of skeletal mets by not allowing that patient to kind of progress? So I think we’ll have to see how that shapes up, because certainly if we’re kind of improving patients’ quality of life, that’s certainly extremely compelling data.
In the second line, our benefit — whether we’re talking about oral SERDs or the PROTAC that’s also approved — has been restricted to ESR1 mutations, and so that’s elacestrant, imlunestrant, vepdegestrant. But you bring up some of the combination data. So whether we’re talking about combining with abemaciclib or a potential combination coming with everolimus.
And so, I think we kind of always have to make decisions based on the patient that’s in front of us right now and what their options are, not kind of banking for the future. We know that unfortunately, a lot of patients do drop out between lines of therapies for performance status reasons, for a variety of reasons, and so I probably am going to be a little bit more compelled to kind of treat that patient based on the data that I have for them right now.
Dr. Kaklamani [0:08:19]: Okay, that’s perfect, and it’s going to really be, I think, a dilemma for clinicians as to what to do, because we have good single-agent data in patients that have a more indolent, potentially, disease, more endocrine-sensitive disease, and then good data both from EMBER-3 and evERA showing that the combinations are giving us a prolonged progression-free survival.
Now we’ve had the SERENA-4 press release last Friday, so very recent. Komal, we now have two first-line trials with oral SERDs, SERENA-4 and persevERA, both of them negative trials. How do you look at that data, especially in the context of our adjuvant trial, the lidERA trial, being positive, and, and what are your assumptions of why these trials ended up being negative, but lidERA is positive?
Dr. Jhaveri [0:09:09]: Oh, what a fantastic question yet again, Virginia, and very, very relevant and important, because I think with more results come in more questions, appropriately. And I think this is a great example for that. So let me refresh our memories and jog our memories together.
Actually, come to think, there are four trials in the first-line space that we have data for. First one was the PARSIFAL trial, which was a phase 2 study where we tried to see if there was an optimal endocrine backbone, and we tried to compare fulvestrant-palbociclib compared to letrozole-palbociclib in a first-line endocrine-sensitive patient population, and that trial did not meet statistical significance in that there was no superiority seen in the fulvestrant arm. And when we looked at long-term seven-year overall survival data, there was no difference in overall survival. So fulvestrant was not worse, but just not better to replace the AI-CDK.
But then we said, “Geez, this is a phase 2 study. We need larger trials. Would it be different with oral SERDs? Should we be studying that question with an oral SERD that’s better than fulvestrant?” And certainly, we tried to do that, right?
And the very first negative readout that we actually saw was from AMEERA-5, which was amcenestrant, which is not, you know, being developed any further because of two negative readouts. But that was also an early futility analysis that the IDMC, you know, pointed out and said there was no benefit seen with the amcenestrant oral SERD, and that was an early readout. It was median follow-up of eight months, but we got that early signal, and then we’re like, okay, it’s not being developed. There was some potential concern about maybe drug-drug interaction with amcenestrant and the CDK. So we wanted to still wait for more definitive studies.
Then came persevERA, and we saw that results being presented at ASCO by Nick Turner, where we saw that there was a numerical five-month gain, but we did not see statistical significance. The hazard ratio was 0.89. Quite mature in data set — median follow-up is 52 months — but we see that the curves don’t even separate up until month 12 or 14. So in the beginning, they are really overlapping, and then there is a narrow separation after 12 to 14 months. So it tells you that there is some lag time before it actually shows some potential numerical benefit.
And now we see the press release for SERENA-4, a larger study, right? 1,371 patients randomized — larger than even persevERA, which was 990 patients — and again we’re seeing a numerical gain, is what we understand from the press release, but not statistical significance. So I think we’re getting more and more data to kind of support the fact that when you’re combining a SERD with a CDK4/6 inhibitor for an all-comer patient population in the upfront setting, you’re not able to identify a benefit for such an approach that can beat our current standard of care with AI-CDK. And that’s the common pattern that we’ve learned.
One other trial that I think will help us answer the question you asked about lidERA: go back and think about FALCON, right? We had the FALCON study that compared fulvestrant with an aromatase inhibitor, and there we showed superiority. We said a SERD was better than an aromatase inhibitor. The hazard ratio, however, was high — it was 0.79 — and the delta of benefit between the two drugs was three months. So it’s like 17 months and 14 months. So yes, there was statistical superiority with single-agent comparison, but the hazard ratio was high. When you add a CDK4/6 inhibitor, you’re diluting that out even more and not able to show that. I think that’s what we’re learning in the first line.
Now, when it comes to lidERA, context is different. We have early stage compared to metastatic stage, meaning we don’t have a resistant clone upfront in the early stage necessarily that we’re thinking about. In the first line, this is a metastatic patient population. There is some resistance that one can expect, either as a primary endocrine resistance, some that get acquired as a secondary endocrine resistance.
But the second important point is, while the contexts are different, we’re also talking about combination trials with CDK in the metastatic setting, and lidERA is not with a CDK4/6 comparison — so I don’t think we can just compare the two. There are two different contexts. Early stage is very different than late stage, and when you combine CDK, it’s very different than endocrine therapy. And we have always seen, even in the early stage, that AI was better than TAM. We don’t have fulvestrant comparisons with AI at the early stage, but even with the AI-TAM, the hazard ratios were high. So this is not surprising that a better endocrine agent beat the older endocrine agent in the early-stage setting.
So I am not necessarily disappointed or confused about the lidERA results. I feel very compelled, and I really look forward to additional follow-up from the lidERA trial to see whatever we saw in the first 32 months in terms of a hazard ratio of 0.7 in a high-risk patient population, how it holds true with longer follow-up.
Dr. Kaklamani [0:14:13]: And thankfully, we’re going to have data from CAMBRIA-2 and other adjuvant trials that’ll help us figure out that space. And so, just to finish off, Erika, give me kind of your prediction as to how we are going to be moving these oral SERDs, PROTACs, into our treatment in the future.
Dr. Hamilton [0:14:31]: Yeah, I think that’s a great question. So, right now the PROTAC, the vepdegestrant, is approved in second line, and it’s for the subset of patients that have an ESR1 mutation. So, very similar to what we see for the oral SERDs, single-agent approvals, elacestrant and imlunestrant.
You know, it is a different mechanism of action. I hear a lot of people kind of grouping it as an oral SERD. It does degrade the estrogen receptor, but it really does so in a unique way, kind of ubiquitinating that estrogen receptor, and the proteasome kind of comes in — and I kind of call it the intracellular garbage disposal, where it’s chomping up and spitting it out — and then that PROTAC molecule is free to kind of go and act on another estrogen receptor. So it has iterative activity.
And so, I think it’s an interesting thought to start thinking about: if we’re using oral SERD in the adjuvant setting for patients that relapse quickly, or if we’re using oral SERD in something like SERENA-6 in a switch strategy in the first line, might there be a competitive advantage in the second line to use something with a little bit of a different mechanism of action like vepdegestrant versus kind of oral SERDs that were traditionally tested in second line?
We certainly don’t have any great data there. I participated in the phase 1 with vepdegestrant. I’ll tell you, certainly not generalizable data: I did treat four patients on that phase 1 clinical trial that had already had an investigational oral SERD, and I did see objective responses with vepdegestrant. So I think it’s possible — whether that’s going to bear out in larger data sets, et cetera, is up for determination. But I do want people to kind of be thinking about that as a little bit of a different twist on estrogen degradation.
Dr. Kaklamani [0:16:17]: Exciting. Exciting for our patients. Okay, well, I want to thank both of you for being with us today, and I want to thank our audience for listening in. And this, as well as a lot of other data, will be discussed at the San Antonio Breast Cancer Symposium this December. Thanks, everyone.
