This transcript has been lightly edited for clarity.
Stephanie Graff, MD: Hi, my name is Dr. Stephanie Graff, and I am a breast medical oncologist, welcoming you back to our San Antonio Breast Cancer Symposium (SABCS) review. We have previously recorded an episode focusing on the PATINA trial. So, this is our “take two,” if you will, looking at EMBER-3, which is one of the other abstracts that we thought was particularly attention-grabbing out of SABCS. I am a breast medical oncologist in Providence, Rhode Island, at Brown University, and director of the Breast Cancer Center at Brown University Health. I’ll let my colleagues introduce themselves. Dr. Cobain?
Erin Frances Cobain, MD: Hi, I am Dr. Erin Cobain. I’m an associate professor of medicine here at the University of Michigan, and I am a breast cancer medical oncologist at the Rogel Cancer Center.
Dr. Graff: And Dr. Bhave?
Manali Bhave, MD: Hi, there, I am Manali Bhave. I am a breast medical oncologist and director of the phase 1 unit at Emory University in Atlanta, Georgia.
Dr. Graff: I’m going to just briefly talk through the EMBER-3 trial, and then I can’t wait to hear each of your thoughts. EMBER-3 is a trial that took a two-pronged approach, looking at imlunestrant either as monotherapy or combined with abemaciclib for patients with estrogen receptor–positive, HER2-negative advanced breast cancer previously treated with endocrine therapy. It was presented at SABCS. And it had this complex statistical design. In order for the imlunestrant plus abemaciclib arm, which is arm C, to be analyzed, either the imlunestrant versus fulvestrant arm (arm 1 or arm A) had to be positive, which was in all-comers, or arm B, which is patients with ESR1 mutations, had to be positive. We actually got all three of those results presented at SABCS.
In the first analysis of progression-free survival in patients with ESR1 mutations, we saw that imlunestrant versus standard-of-care endocrine therapy improved progression-free survival from 3.8 months with standard-of-care endocrine therapy to 5.5 months with imlunestrant, meeting statistical significance, with a hazard ratio of 0.62. All subgroups seemed to benefit, including those with visceral metastasis and prior CDK4/6 inhibitor use.
In the second group, which was imlunestrant versus standard of care in all patients, regardless of whether or not they had an ESR1 alteration or not, imlunestrant improved progression-free survival, but just barely. It was 5.5 months with standard-of-care endocrine therapy versus 5.6 months with imlunestrant, which did not meet the prespecified hazard ratio. The hazard ratio was 0.87. The prespecified hazard ratio was 0.84. So it was not statistically significant for all-comers, only statistically significant in the ESR1-altered population for the benefit of imlunestrant. This is similar to what we’ve seen with the other oral selective estrogen receptor degraders (SERDs) we have now. At least in the United States, we have approval for elacestrant in the ESR1-altered population.
However, that did trigger the analysis for imlunestrant plus abemaciclib versus imlunestrant in arm C. And what we saw was that the combination of imlunestrant plus abemaciclib significantly improved median progression-free survival from 5.5 months for imlunestrant alone to 9.4 months for patients randomly assigned to receive imlunestrant plus abemaciclib, with a hazard ratio of 0.57. Again, it was statistically significant. The progression-free survival at six months was 40% to 66%. At 12 months, it was 27% to 42%. Again, all subgroups benefit on the breakdown of the forest plot, including prior CDK4/6 inhibitor use, visceral metastasis, and both ESR1-altered and PI3 kinase–altered pathways, all seem to benefit.
They did give us some nice subgroup breakdown, including patients with and without ESR1 mutations, patients with and without prior CDK4/6 inhibitor use, and really highlighting that it seemed that everyone benefited. And interestingly there was a small signal – very exploratory – that seemed to suggest there was some good central nervous system activity with the combination regimen.
Overall survival data are immature. One of the things that I thought was good to see was the safety and tolerability for imlunestrant in particular, which was well tolerated. Less gastrointestinal toxicity than we have seen reported with the other oral SERDs and none of the class side effects that we’ve come to anticipate with SERDs – things like bradycardia or the photopsia, the eye side effect that sometimes patients have been reporting with oral SERDs. It is a very well-tolerated oral SERD. The combination saw mostly the side effects that we already know and associate with abemaciclib.
For me, in conclusion, I think that this is a very favorable study for imlunestrant. And I think that the combination looks really, really promising. I am at the edge of my seat waiting to see what regulators do with this information, which is where I’m going to pass it to my colleagues here to see what your takes are coming out of SABCS. I will mention, of course, it was published synchronously in the New England Journal of Medicine.
Dr. Bhave: Yeah, I agree with you, Stephanie. I felt like these were really promising and exciting data. I do want to point out that this was a study looking at this oral SERD in the second-line setting. So, this was after progression on a first-line aromatase inhibitor (AI), with or without a CDK4/6 inhibitor, and there was no other endocrine therapy or chemotherapy allowed prior to enrollment. This is going to be earlier on in the course where we do have some other endocrine options as either monotherapy or combination strategies to select from.
I was also very curious to see the ESR1 data. I think based off the phase 1 data on imlunestrant, it was not clear whether the benefit with monotherapy would only be in that ESR1-mutated population or in the overall population. I think you’re right; we are seeing similar results to what we saw with our other oral SERDs. There was a statistically significant and more meaningful benefit in those patients with ESR1 mutations.
I also think the combination strategy was very promising. We saw a very low discontinuation rate – I think somewhere around 6%, with a combination of abemaciclib and imlunestrant. This is particularly a promising strategy in patients who might have seen a CDK4/6 inhibitor in the adjuvant setting and were still allowed to enroll in this study. I think, overall, it is very exciting to have an all-oral-therapy option for these patients. Like you said, we’re waiting on the regulatory bodies to assess whether both the combination and the monotherapy arms will be for patients who have ESR1 mutations or whether we are going to see differences in eligibility for the combo versus the single-agent imlunestrant.
Dr. Cobain: I agree with and will echo what both of you have just said. Just a few other thoughts to add here. One of which is that I just think it was really exciting in general to see combination data with an oral SERD. This is really the first abstract we have seen presented where the oral SERD has been in combination with a targeted agent and not as monotherapy. I think the reason that is so important is because I think all of us feel in clinical practice that the utility of the oral SERDs will very likely be in combination and not as a monotherapy.
We are stuck in this position right now where the only FDA approval we have for an oral SERD, with elacestrant, is as a monotherapy for patients with an identifiable ESR1 mutation. It is a very select group of patients that we are able to use elacestrant in. Even still, I think that in those patients who have an ESR1 mutation, sometimes you wish you had something additional to add to the elacestrant. Because some of the benefit that we are seeing from that therapy may not be as sustained as we would anticipate it might be, if we were able to administer that therapy in combination with another targeted agent. I think that is one of the reasons that this data is exciting.
I think one of the things that is interesting is that obviously this study did not require prior CDK4/6 inhibitor use. The vast majority of our patients that we will see in clinical practice, if this ultimately does get approval, will have probably been exposed to prior CDK4/6 inhibitor. I think there were about 20%–30% of patients in the trial who had not had a prior CDK4/6 inhibitor. Something to keep in mind as we potentially apply this moving forward is that this trial population is potentially not universally reflective of the patient population that we are likely to see in our clinic, who we might be thinking about for these therapies.
Then the third comment that I would make is that undoubtedly the data on imlunestrant alone clearly has a more profound benefit for those with an ESR1 mutation. That is clear, just as we have seen with many other oral SERDs. I think it is important to keep in mind that it does not mean that the oral SERD does not work for the wild-type populations. It may just mean that it is equivalent or roughly equivalent to fulvestrant. I think that that is an important thing to remember, just because there are many patients who probably would prefer oral therapy over getting a monthly injection.
I too am very eager to see what the U.S. Food and Drug Administration (FDA) does with this information. Because when we previously got the FDA approval only for those with an ESR1 mutation, I think some of us were a bit surprised by that decision. That is only because I think that if there truly is equivalence among patients who are wild type for ESR1, I think many of our patients would love to have the option of an oral therapy as opposed to the monthly injection. I think it will be interesting to see how that develops and if this becomes available ultimately for all-comers.
Dr. Graff: Can I just follow that up? Is there a hormone-sensitive breast cancer theorem, if you will, that can be built here using EMBER-3 and postMONARCH? postMONARCH taught us that after a CDK4/6 inhibitor, abemaciclib plus fulvestrant is better than fulvestrant alone. And EMBER-3 taught us that after any endocrine therapy, including sometimes prior CDK4/6 inhibitors, imlunestrant is better than fulvestrant alone if you have an ESR1 mutation. And imlunestrant plus abemaciclib is better than imlunestrant alone, regardless of what your mutational status is. The combination of those theorems – if one then two, then three equals seven – that combination arm (imlunestrant plus abemaciclib) is a logical step after progression on AI plus CDK4/6 inhibitor. I keep trying to bend that together, and I think it logically makes sense. But I’m not sure that I quite got all of my math put together to make it into the mind of a regulator.
Dr. Cobain: Yeah, I agree with you. I think that some of the challenge in this second-line space is about what you do with the patient who has other targetable alterations – individuals who have activating PI3-kinase mutations or an AKT1 mutation or loss of PTEN who are otherwise candidates for alpelisib or capivasertib. I think the second-line endocrine therapy space in metastatic disease is just becoming incredibly complex. It is wonderful to see all of these exciting data and these combinations that are having positive trial results. But I think we just have to acknowledge that the logical next step for our patients following progression on an AI and CDK4/6 inhibitor is becoming something where the waters are increasingly muddied.
Dr. Graff: Dr. Bhave?
Dr. Bhave: Yeah, I completely agree with that, too. I think your logic is how I was thinking through the combination of abemaciclib and imlunestrant as well. I think that would be a really nice option for patients who have no targeted therapy options, but also in those patients with targeted therapy options who may not tolerate or be eligible for those targeted therapies.
I do foresee us likely using that combination, probably relying on that combination more heavily than imlunestrant monotherapy. I echo everything that Dr. Cobain said, too. We are waiting now on data with our approved oral SERD, elacestrant, in combination with targeted therapies as well, which might continue to muddy the water but give us options for our patients. We can discriminate through those options based off of mutational status, functional status, comorbidities, toxicity profiles, et cetera, which I think will put us in a better place and will allow for more personalized care and better outcomes for our patients.
Dr. Graff: Yeah, I can’t wait to see how this space evolves as new drugs continue to emerge. Of course, at SABCS, we also saw a bunch of posters and follow-ups on the emerging CDK2 and CDK7 landscape and new selective PI3 kinase pathway therapeutics. I think that this will continue to get more complicated for all of us, as the alphabet soup of second-line hormone receptor–positive breast cancer takes shape over the coming years. But it is a great time to have new therapies to hopefully revolutionize patient care, patient experience, and long-term outcomes.
Thank you both for sharing your thoughts, your Leading Thoughts, with us today. I look forward to talking to you again soon.
Dr. Bhave: Thank you.
Dr. Cobain: Take care. Thanks.
