Dr Komal Jhaveri:
Welcome to The ASCO Post Roundtable Series on the Role of Oral SERDs in Metastatic Breast Cancer. I'm Dr Komal Jhaveri, and I'm a breast medical oncologist at Memorial Sloan Kettering Cancer Center in New York. Very happy to be joined today by two of my esteemed colleagues, Dr. Hamilton and Dr Bardia who'll introduce themselves as well.
Dr. Erika Hamilton:
Hi, I am Dr. Erika Hamilton. I'm the Director of the Breast Cancer Research Program and Chair of the Breast Executive Committee at Sarah Cannon Research Institute in Nashville, Tennessee. Happy to join both of you today.
Dr Aditya Bardia:
Hi, I'm Aditya Bardia, medical oncologist at UCLA. Excited to be here today.
Dr Komal Jhaveri:
Thank you so much both. So today we'll be discussing the use of oral SERDs in the treatment and management of metastatic breast cancer with three patient case studies. Our second installment will focus on a second-line treatment for a patient with ER-positive HER2-negative metastatic breast cancer whose tumor harbors an ESR1 D538G mutation after progression on a CDK4/6 inhibitor.
So we have MR, who's a 67-year-old post-menopausal woman with ER-positive HER2-negative metastatic breast cancer. She received first-line therapy with palbociclib and an aromatase inhibitor. And this was for de novo metastatic breast cancer presentation. But after 22 months on that first-line therapy, developed asymptomatic progression in the bone, and also developed three new liver lesions that were detected on imaging.
ctDNA testing was performed, and revealed presence of an ESR1 D538G mutation, and no other actionable alterations, specifically no PIK3CA, AKT, or PTEN alteration. There was no evidence of germline BRCA1 or 2 mutations either.
So assuming again all options are available to us in clinic, which second-line therapy would you prefer for this particular patient? Your options include fulvestrant with abemaciclib, fulvestrant with everolimus, monotherapy with elacestrant, monotherapy with imlunestrant, abemaciclib with imlunestrant. Maybe, Dr Bardia, you could walk us through your thought process here?
Dr Aditya Bardia:
Absolutely. It's one of the scenarios where all the options are correct. You can make a case for any of these options. I'll start with an oral SERD first.
We have data from the EMERALD trial, particularly looking at the subgroup of patients who had ESR1 mutations, and in the first-line setting when they were on CDK4/6 inhibitor, if they were on the CDK4/6 inhibitors for more than 12 months, like this patient with elacestrant, medium PFS was about 8 to 9 months. So that's certainly an option to consider.
You can also make a case for imlunestrant. We've seen data from EMBER-3 does activity in this setting, as well as imlunestrant plus abemaciclib, which has even better efficacy than imlunestrant alone.
You can make a case of fulvestrant plus abemaciclib from the post-MONARCH data, where the combination of fulvestrant/abemaciclib in the post-CDK4/6 setting had activity. And then finally fulvestrant plus everolimus, which I would prefer over exemestane/everolimus in this scenario. Given the ESR1 mutation, I generally like a SERD backbone as opposed to AI. So everolimus with fulvestrant is a reasonable option to consider as well.
So how would I choose between these options? It's a patient-centered discussion presenting the options, talking about the side effects. If a patient prefers single-agent therapy then elacestrant or imlunestrant, both would be very reasonable options to consider as monotherapy.
Dr Komal Jhaveri:
Fantastic. Dr. Hamilton, maybe I'll push you a little bit more. I think we should add one additional option here, based on the data you presented and published as well on vepdegestrant and a PROTAC, which also showed monotherapy activity in ESR1-mutant tumors. So maybe we should add that to the mix here as well and see if that was also available.
What I'd love to hear from you is, if you have more than one option, even as monotherapy, how would you decide between those? And between monotherapy and combination therapy in such a scenario, is there a way to really figure out what might be the best approach for a given patient in clinic? And lastly, how does adverse event really help you make this decision for a patient?
Dr. Erika Hamilton:
Yeah. I think that that's a fantastic question. It's really only our patients that have ESR1 mutations that kind of have the advantage of maybe not needing combination therapy. Certainly our patients that have PI3, AKT, PTEN alterations, they need combination therapy. Our wild-type patients aren't doing as well on single-agent endocrine therapy as we really want them to be. And so that's really where I think where we get into combinations with everolimus, or combinations with CDK after CDK, like abemaciclib. So I do think that this is a patient that is kind of a really good thought for single-agent oral SERD or PROTAC that may be better tolerated than the combinations.
When we get into how to tease this data out, I think it's a toss-up. I think all of these agents have activity. I think the imlunestrant data to me at least looked very compelling with the combination of abemaciclib. I did note that in the single-agent, that about a third of patients hadn't seen a CDK4/6, so it was kind of hard to compare that PFS apples to apples. The vepdegestrant and the elacestrant data is pretty similar. Fulvestrant control arm was 1.9 months on elacestrant, 2.1 months on vepdeg. And then the SERD or PROTAC with elacestrant was 3.8 months, and with vepdegestrant it was 5.0 months.
I guess if I had to say, I would pick vepdegestrant, part of that is probably just that I have a lot of experience using it, and have been using it for quite some time. I also find it a little bit difficult to tease out a gastrointestinal side effects with the oral SERDs. They're clearly not all the same drug. We do think of it as kind of a class side effect, but some tend to have less than others. And so that was something that I was pretty pleased with was that vepdegestrant, really seeing any-grade vomiting, any-grade diarrhea at only 6%. So I think it was a well-tolerated option.
Dr Komal Jhaveri:
I completely agree. And yeah, no, I think you summarized it very beautifully. I do think they are kind of similar-ish overall. I do think there are some nuances to their low-grade toxicity profiles. Thankfully these are all low-grade toxicities. You see some low-grade QTc or bradycardia with some drugs, and photopsia with some drugs such as camizestrant. Nothing clinically impactful or necessarily interfering with the patient's quality of life or independent daily activities of living, but having said that, there are some nuances. Some nausea more with elacestrant for instance, or a little bit more diarrhea with imlunestrant, and maybe QTc with vepdegestrant. So I feel like there are some nuances to them. I agree the comment about efficacy as well.
I do have to say, I have been tempted with the data from EMBER-3 with the combination, even in ESR1-mutant tumors, which was 11.1 months. So while I feel like I'm very enthused about the monotherapy data, and we know that that's the right patient who stays on a CDK4/6 for a long period of time and has an ESR1 mutation, it's tempting to see if patients can tolerate imlunestrant, which I think we've really learned to manage well, that maybe we can even get more by getting this ESR1 mutation targeted with two drugs based on the data set.
So yeah, I think it's something that we would discuss with the patient, and make a physician/patient decision-making process. But overall, I completely agree that you can reach out for monotherapy here and we have more than one option. And we might have some personal preferences the way we do with say the choice of aromatase inhibitor, or choice of a CDK4/6 inhibitor at some degree, and now even to TROP2 ADCs if you will, for endocrine refractory patients. So completely agree with this discussion.
So I think in terms of what did we learn or what is the clinical takeaway from this patient's presentation? I think one thing we have learned is that monotherapy oral SERDs are very important to consider, especially for patients who stay on their CDK4/6 inhibitor for a long duration of time. And then the tumors harbor an ESR1 mutation, and necessarily no other co-occurring alteration that you worry about. And those are the patients that might benefit very easily from this very well tolerated therapies for a longer duration of time.
Certainly, there is now emerging data for combination-based therapies here as well in ESR1-mutant tumors. And that would be a great discussion to have with patients, to discuss the additional toxicity that a combination regimen could bring compared to just monotherapy oral SERD.
And then, while we are going to have more than one oral SERD potentially available in clinic, I think this is, again, going to be a patient/physician decision-making process, based on the slightly distinct toxicity profiles, and maybe the data that we have with respect to efficacy and distinct patient population, knowing that we cannot make any cross-trial comparisons. So thank you again for that.
So I would say this brings us to the end of this case. Please see the other segments for further discussion about the latest research in metastatic breast cancer, or visit ascopost.com. Thank you.
