Imlunestrant with or without abemaciclib in advanced breast cancer: Results of the Phase III EMBER-3 trial

Jhaveri KL et al. Imlunestrant with or without abemaciclib in advanced breast cancer. N Engl J Med 2025;392(12):1189-202. Abstract 

Jhaveri KL et al. Imlunestrant, an oral selective estrogen receptor degrader (SERD), as monotherapy & combined with abemaciclib, for patients with ER+, HER2- advanced breast cancer (ABC), pretreated with endocrine therapy (ET): Results of the Phase 3 EMBER-3 trial. San Antonio Breast Cancer Symposium 2024;Abstract GS1-01.

DR LOVE: Welcome to 5-Minute Journal Club, Oral SERDS edition. This is medical oncologist Dr Neil Love.

On this program, I met with Dr Rinath Jeselsohn from the Dana-Farber Cancer Institute for her comments on some of the most important recent publications and presentations on this new and evolving therapy for hormone receptor-positive breast cancer, beginning with a key presentation and immediate publication in the New England Journal of the Phase III EMBER-3 trial, evaluating the as-yet-unapproved oral selective estrogen receptor degrader imlunestrant.

DR JESELSOHN: EMBER-3 was a trial that looked at patients who had up to 1 prior line of endocrine therapy and allowed prior treatment with a CDK4/6 inhibitor, advanced or metastatic ER-positive, HER2-negative breast cancer, were randomized to either fulvestrant, imlunestrant or imlunestrant plus abemaciclib. And the primary endpoints were comparing imlunestrant versus fulvestrant in patients and also imlunestrant plus abemaciclib versus fulvestrant. For the comparison of imlunestrant versus fulvestrant, there was an improvement in progression-free survival when looking at patients with ESR1 mutations.

And then for the combination of abemaciclib plus imlunestrant versus imlunestrant alone, there was an improvement with the addition of abemaciclib to imlunestrant for the entire patient population.

DR LOVE: So one of the things that was interesting was that they all had to have prior endocrine therapy, but a significant number, I think around a third, had not had CDK.

DR JESELSOHN: Right.

DR LOVE: And you could understand why using a CDK like abema would be helpful in those patients, but what about the patients who did have CDK?

DR JESELSOHN: When they looked at those subgroup analyses they showed that having prior CDK4/6 inhibitors did not really matter, so patients who had prior CDK4/6 inhibitors also did better with the addition of abemaciclib plus imlunestrant versus imlunestrant alone.

DR LOVE: So we actually did 3 CME programs at San Antonio, so I had the opportunity to ask faculty right on the spot, and so I’m going to ask you the 2 questions I asked to the faculty and compare what you say to what they said.

So the first question I asked them was, would you like to have imlunestrant monotherapy available, and if so, in what situations would you use it?

DR JESELSOHN: Yes. I think the data shows that imlunestrant as monotherapy for patients with an ESR1 mutation could be a potential treatment. Who are the patients that benefit from a monotherapy endocrine therapy, specifically patients with an ESR1 mutation?

We have some data from subgroup analysis from elacestrant. We know that patients who've had disease stability on prior endocrine therapy plus CDK4/6 inhibitors for at least 12 months, those patients did better with single-agent endocrine therapy. So I think that is 1 criteria that’s important to include in your decision-making about monotherapy endocrine therapy in a patient with metastatic ER-positive breast cancer with mutant ER.

In addition, there are other clinical factors, such as how much disease burden, visceral involvement, liver metastases involvement that also need to be taken into account when thinking about who is a good candidate for monotherapy endocrine therapy for ESR1-mutant patients.

DR LOVE: So — and that reflects the way the faculty at San Antonio responded when I asked them, but also the question of, if you had imlunestrant monotherapy and elacestrant monotherapy both available, in what situations would you use one versus the other? Would it be, like, a letrozole/anastrozole coin flip?

DR JESELSOHN: Yeah. I think it would be like a letrozole/anastrozole coin flip at this time. We really don’t have head-to-head comparison.

DR LOVE: So the other question, of course, that I asked the faculty was, would you like to be able to use the combination with imlunestrant and abemaciclib, because I had no idea what they were going to say. I was kind of surprised they all said yes to that. What do you say? Would you like to be able to use that combination?

DR JESELSOHN: I think the data of imlunestrant plus abemaciclib with a PFS of 9.4 months is very compelling. There are patients that receive fulvestrant as their first-line endocrine therapy in metastatic disease, for which having abemaciclib plus imlunestrant would be very useful. So yes, I think there are certain situations where we would want to combine abemaciclib with imlunestrant, but I think we still don’t know if for a larger patient population, is abemaciclib plus imlunestrant really better than fulvestrant plus abemaciclib?

DR LOVE: If you could, are there situations where you’d use that combination first line?

DR JESELSOHN: That’s a hard question. Where I think there might be an added benefit is really for patients with ER mutations for this combination, but again, we don’t have that data, so it’s hard to know.

DR LOVE: What about in a patient who’s had a CDK inhibitor, so second line? We have the postMONARCH data in the background here. Again, are there situations in a patient with prior CDK as second-line therapy you want to use the combination of imlunestrant with abemaciclib? And would it depend on which CDK inhibitor they got first?

DR JESELSOHN: Yeah. So I think the postMONARCH data is really pointing to the fact that abemaciclib is different from palbociclib. So most of the patients in postMONARCH did receive palbociclib as their first-line CDK4/6 inhibitor, and the postMONARCH data did show clinical benefit to the addition of abemaciclib to fulvestrant in that setting.

Is abemaciclib post-abemaciclib still useful when switching the endocrine therapy backbone? I think that’s a good question that we don’t know yet.

I do want to add also, I mean, there is additional benefit for imlunestrant versus fulvestrant, and imlunestrant is an oral medicine, and for some patients the injections are very uncomfortable. And also they do require monthly visits, whereas with an all-oral combination, we can potentially reduce the number of visits and improve patients’ quality of life.

Comprehensive genomic profiling of ESR1, PIK3CA, AKT1 and PTEN in HR-positive, HER2-negative metastatic breast cancer: Prevalence along treatment course and predictive value for endocrine therapy resistance in real-world practice

Bhave MA et al. Comprehensive genomic profiling of ESR1, PIK3CA, AKT1, and PTEN in HR(+)HER2(-) metastatic breast cancer: Prevalence along treatment course and predictive value for endocrine therapy resistance in real-world practice. Breast Cancer Res Treat 2024;207(3):599-609. Abstract

DR LOVE: The next paper, published in Breast Cancer Research and Treatment, is another in the many real-world analyses that have been recently proliferating in the oncology literature.

DR JESELSOHN: This was a real-world study. This was looking at patients with metastatic ER-positive breast cancer with Foundation Medicine, looking specifically at ESR1 mutations as well as mutations of the PI3 kinase pathway, including PIK3CA, AKT and PTEN.

So first of all, they did a quite extensive analysis of the ESR1 mutations. They showed nicely that the ESR1 mutations are really acquired, so they’re not very common at the time of diagnosis of metastatic disease or when a patient is starting first-line treatment, and then we start seeing them more prevalent as patients receive more treatment in metastatic disease. And this has been shown previously, that really they are acquired, mostly in metastatic disease and mostly post-treatment with an aromatase inhibitor.

They also showed that PTEN deletions are better detected in tissue biopsies versus ctDNA, and that’s not really that surprising, because ctDNA, many times it’s very difficult to look at copy number alterations with ctDNA, and you really need a very high tumor fraction to be able to detect them. So for those type of alterations, tissue biopsies right now are probably better.

DR LOVE: What do we know about the incidence of ESR1 mutations in patients with prior adjuvant endocrine therapy and then first-line metastatic disease?

DR JESELSOHN: Yeah. So the ESR1 mutations starting from early-stage disease are fairly rare. We see them in about up to about 3% of patients. So these are treatment-naïve patients. There have been small neoadjuvant trials of endocrine therapy where they saw actually in neoadjuvant treatment acquisition of the ESR1 mutations. Again, very small numbers.

When a patient presents with early-stage disease after adjuvant treatment, in most cohorts the percent of ESR1 mutations are found in around at most 10% of patients.

We had done an analysis a few years ago, and we presented it at ASCO, that patients who actually have what’s called endocrine primary resistance, so they developed recurrences very early on during adjuvant endocrine therapy. In those patients, we found that the prevalence of the ESR1 mutations is actually higher, at around 15% of patients. So there might be a subgroup of patients where at first-line treatment of metastatic disease the ESR1 mutations are more prevalent.

One hypothesis could be the longer adjuvant therapy you get potentially the higher chances you will get an ESR1 mutation because they are acquired during that time.

On the other hand, if a patient has an ESR1 mutation detected at primary disease, those patients are more likely to develop an earlier recurrence, because they’re potentially resistant to adjuvant aromatase inhibitors. And that’s why potentially we are seeing those mutations at a higher frequency, because they might have had a mutation up front.

Camizestrant, a next-generation oral selective estrogen receptor degrader (SERD), versus fulvestrant for postmenopausal women with estrogen receptor-positive, HER2-negative advanced breast cancer (SERENA-2): A multi-dose, open-label, randomized, Phase II trial

Oliveira M et al. Camizestrant, a next-generation oral SERD, versus fulvestrant in post-menopausal women with oestrogen receptor-positive, HER2-negative advanced breast cancer (SERENA-2): A multi-dose, open-label, randomised, phase 2 trial. Lancet Oncol 2024;25(11):1424-39. Abstract

DR LOVE: The next paper is from Lancet Oncology and focuses on another yet-unapproved oral SERD, camizestrant, which is also the focus of an upcoming ASCO plenary presentation on another study of this agent, the Phase III SERENA-6 trial. But the Lancet Oncology article describes the Phase II comparison, the SERENA-2 study, comparing camizestrant to fulvestrant.

DR JESELSOHN: Camizestrant is another oral SERD. Its chemistry is a little different. We’ve been studying these compounds in the lab, and as far as when we compare their ER degradation activity, overall they’re quite similar; when we look at their antagonistic activity, they’re quite similar. So when we look in the lab in cell ions those are all we’re seeing, quite similar activity. So again, it’s going to be hard to say if any of them at the end of the day, as far as clinical efficacy, is going to be different.

We do know that camizestrant ’s side-effect profile is a little bit different. There are some unique side effects with this SERD, particularly there are some vision changes, specifically this photopsia that they’re seeing, which is reversible. Once you stop the drug, it goes away. They haven’t seen significant vision changes. They’re also seeing some bradycardia, again, low-grade bradycardia, but they are seeing that. So this drug does have a side-effect profile that seems to be a little bit different than the others.

They showed that both the camizestrant at 75 mg as well as camizestrant at 150 mg had an improved progression-free survival compared to fulvestrant. So this study was designed to look at the entire patient population. It wasn’t designed to look specifically at ESR1 mutations. And this added benefit with camizestrant was seen in the entire patient population.

Again, I think we cannot compare these results to other studies, because the inclusion criteria and the patient population is very different in this study.

DR LOVE: So you mentioned the photopsia, and I’m curious what patients actually describe.

DR JESELSOHN: Basically, they’re saying that when changing from light to dark, they’re seeing flashes. Tamoxifen also can cause ocular changes.

DR LOVE: Wow. I didn’t know that.

DR JESELSOHN: And they’re rare. Yeah. They are rare. In addition, it can have some changes in the nerve. They’re very, very rare. So it’s interesting why some of the endocrine therapies have ocular changes, and I think understanding that could be helpful.

DR LOVE: Wow. I did not know that. That’s really interesting.

Speaking of tamoxifen, I was going to ask you before, does tamoxifen work better or differently in people with ESR1 mutations?

DR JESELSOHN: Yeah. So that’s a great question. We don’t have much clinical data on tamoxifen and ESR1 mutations, because we don’t commonly use tamoxifen anymore in the metastatic setting where we see the ESR1 mutations, so I am not aware of any large clinical study looking at tamoxifen and ESR1 mutations. Preclinically there are biophysical studies looking at how do the ESR1 mutations affect tamoxifen, and there is data showing that they can decrease the affinity to tamoxifen and the efficacy of tamoxifen.

Latest on SERDs: An education session at San Antonio Breast Cancer Symposium 2024

Jeselsohn RM. Latest on selective estrogen receptor degraders (SERDs). San Antonio Breast Cancer Symposium 2024;Education Session 5.

DR LOVE: The final paper of this issue of 5-Minute Journal Club focuses on a presentation by Dr Jeselsohn at the 2024 San Antonio Breast Cancer Symposium providing an overview of the current status and future use of oral SERDs in breast cancer treatment.

DR JESELSOHN: My talk focused on SERDs, and it’s important to understand what their mechanism of action is.

They are antagonists, and that’s their main activity, probably, where they basically compete with estradiol for binding to the estrogen receptor, and by that they function as antagonists. And another mechanism of action is the ER degradation, or the estrogen receptor degradation.

At this point really in the field it’s really a question of how much is the degradation really important for the activity of the SERDs. We know the antagonistic activity is clearly important but really unclear if actually the degradation activity is so important, and preclinical studies that have been done demonstrated that potentially the degradation actually might not be really the determinant of the activity of SERDs.

The novel SERDs that are in development, we have elacestrant that has been approved, and I know we’re going to talk about imlunestrant as well. They all do very similar things, but their structure is different, and there might be some nuances that are different between them, but we don’t know those yet. What we do know now is that the side-effect profile is slightly different.

DR LOVE: So you started out here with kind of a shocker, telling me that SERDs aren’t mainly working through degradation of the receptor. But let me ask you, does that apply also to fulvestrant?

DR JESELSOHN: Yeah. It’s the same thing with fulvestrant as well.

DR LOVE: Wow.

DR JESELSOHN: Yeah. So I think we really should be calling them maybe SERADS — selective estrogen receptor antagonists and degraders.

DR LOVE: Huh. Interesting. Where does ESR1 mutant fit in?

DR JESELSOHN: Sure. So we and other groups have identified these mutations — about, now, as key mechanisms of resistance in metastatic disease, about 10 years ago.

So the ESR1 mutations are mutations in the ligand binding domain, and what they do is really they affect the helix 12, and by affecting that component of the ligand binding domain they stabilize the estrogen receptor in active confirmation even without estradiol binding. And that really leads to the constitutive activity of the estrogen receptor even without estrogen.

Another point that’s important to highlight is not only are they resistant then to estrogen deprivation, which means they’re resistant to aromatase inhibitors, but also, they have a decreased affinity to fulvestrant as well, and that’s what leads to the relative resistance to fulvestrant that we’re seeing both in preclinical studies as well as now in the clinic when we look at single-agent fulvestrant. So in the lab, if we give higher concentrations of fulvestrant, we can overcome that resistance. In the clinic it’s a little hard to give much higher concentrations of fulvestrant given the limitations of the bioavailability of fulvestrant.