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. I'm a breast medical oncologist at Memorial Sloan Kettering Cancer Center in New York. And really excited that I'm joined today by two of my colleagues, Dr. Hamilton and Dr. Bardia.
Dr. Erica Hamilton:
Hi, I'm Dr. Erica 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 you guys today.
Dr. Aditya Bardia:
Same here. Aditya Bardia, breast medical oncologist at UCLA and very excited about the discussion 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 first installment will focus on the first-line treatment of a patient with hormone receptor–positive, HER2-negative metastatic breast cancer whose tumor is harboring an ESR1 Y537S mutation. So let's start with that case and talk about more specifics about this patient.
So S.D. is a 61-year-old postmenopausal woman who underwent a mammogram and ultrasound that revealed a 2.5-cm mass in the breast and an enlarged suspicious axillary lymph node as well. She underwent lumpectomy and adjuvant chemotherapy followed by adjuvant radiation and adjuvant aromatase inhibitor. She completed 5 years of aromatase inhibitors, and 18 months after completing her adjuvant aromatase inhibitor therapy, she developed and presented with right hip pain. A bone scan was performed at that time that revealed lytic bone lesions. CT scan of the chest, abdomen, pelvis was also performed and revealed numerous liver and bone metastases involving spine, hip, and ribs.
A liver biopsy was then conducted that showed ER-positive, PR-negative, HER2-negative carcinoma consistent with her primary breast tumor. Circulating tumor DNA testing was done and revealed an ESR1 Y537S mutation with no other actionable alterations. Germline testing was done and there was no BRCA1 or 2 mutation. Liver function panel was normal. With respect to her past medical history, comorbidities included ventricular tachycardia and she was being treated for that with disopyramide. Also has a history of bipolar disorder which was controlled on quetiapine therapy. A baseline EKG had a QTcF value of 440 ms.
So let me turn this over and talk about what kind of treatment options would we want to consider for this patient. Now let's assume for today's discussion that all the options listed here are in fact available to offer our patients in clinic. Which first-line therapy would we recommend for this patient with this HR-positive, HER2-negative metastatic breast cancer, whose tumor is harboring this ESR1 Y537S mutation 18 months after completing an adjuvant aromatase inhibitor therapy. The options are abemaciclib with an aromatase inhibitor, ribociclib with fulvestrant, elacestrant, imlunestrant or imlunestrant plus abemaciclib. So maybe I'll turn it over to you Dr. Hamilton? Any thoughts about what you would want to do?
Dr. Erica Hamilton:
Yeah, we're certainly not going to go for the easy cases today I can see. There's a couple of things that I'm thinking about for this patient. She did not relapse quickly on her adjuvant AI. She completed her 5 years, she's been off 18 months. So I am definitely thinking that I want to give her a CDK4/6 inhibitor. But then she also has this psychiatric history and cardiac history with two medications that are known to cause QTc prolongation. So I potentially would be kind of thinking fulvestrant plus ribociclib for her, but in that scenario it makes me nervous with ribociclib despite the fact that her QTc is normal. So that's a situation that I'm probably thinking about abemaciclib or palbociclib instead. And then even more complicating, we have an ESR1 mutation, which quite honestly is pretty rare in the first-line setting, less than 5%.
We have some mixed data. We certainly know that ESR1s can refer resistance to aromatase inhibitors. Then we have some data that maybe in the combination with CDK4/6 it matters a little bit less. But that's kind of why I would be thinking about a fulvestrant. So if everything was approved, I guess I might even be thinking about an oral SERD for her, imlunestrant with abemaciclib. I'm not liking option 3 and 4 because it doesn't have a CDK4/6. I'm a little bit nervous about option 2 with her QTc and our option one with an aromatase inhibitor. I would kind of prefer a SERD with her ESR1.
Dr. Komal Jhaveri:
Thank you so much for walking us through that and Dr. Bardia, any thoughts on that?
Dr. Aditya Bardia:
Yeah, I fully agree with the thought process that Dr. Hamilton outlined. This patient has ESR1 mutation. So in that setting in general we would prefer a SERD over an AI because that confers estrogen independence. The tumor is still ER-dependent but estrogen-independent. So I would like a SERD with a CDK4/6 inhibitor and the options are palbociclib, ribociclib, abemaciclib; with her history, abemaciclib is very reasonable to consider. Right now the CDK4/6 inhibitors are only approved with fulvestrant, so hands are bit tied in terms of using fulvestrant plus a CDK4/6 inhibitor, but in the future, as you mentioned, if all these drugs are approved, I would prefer an oral SERD particularly for this ESR1 mutation because it's Y537S, which we know confers resistance to fulvestrant and an oral SERD would be much better. So my preference would be an oral SERD with a CDK4/6 inhibitor.
Dr. Komal Jhaveri:
Thank you so much for offering that. So say if we had an additional option of fulvestrant and abemaciclib here as well, you would prefer an oral SERD given this particular Y537S mutation as well. Is that what you were trying to highlight?
Dr. Aditya Bardia:
Exactly.
Dr. Komal Jhaveri:
Thank you. And in general, how is the thought process? How are you thinking about monotherapy and now we're beginning to see these combination regimens with these novel endocrine agents as well. Right? How are you thinking about utilizing monotherapy for a given patient vs utilizing combination therapy? Does that thought process differ between first- and second-line setting as well?
Dr. Aditya Bardia:
Yeah, in the first-line setting, I generally lean towards a CDK4/6 inhibitor combination given that we've seen improvement in overall survival with CDK4/6 inhibitor, at least ribociclib. So unless there's a contraindication not to use a CDK4/6 inhibitor, my preference is to consider combination therapy in the first-line setting.
Dr. Komal Jhaveri:
Yeah, Dr. Hamilton, any other thought there?
Dr. Erica Hamilton:
Yeah, I completely agree. Typically, when we're talking about ESR1 mutations, we're kind of in the second-line setting, so it's a little bit of a twist, but agree. I am really wanting to get CDK4/6 multiple trials where we see an overall survival benefit in that setting. This appears to be a patient that has endocrine-sensitive disease, did well on her AI, relapsing 6.5 years after diagnosis. So this is the type of patient that I think is going to get benefit from CDK.
Dr. Komal Jhaveri:
Makes sense. And while EMBER-3 provided the evidence for the activity of imlunestrant with abemaciclib and allowed both first- and second-line patients, I think in theory we know that we would be utilizing that kind of a strategy predominantly for second line, which was majority of the patients. Only 30% of the patients in EMBER-3 did get this in the first line. But these were patients that had recurred on or within 12 months of their adjuvant endocrine therapy. So slightly different than this particular patient. I think what is unique about this presentation is that while the recurrence is not within 12 months of their adjuvant endocrine therapy, it's beyond that, the ESR1 mutation, as you pointed out, it's rare. It's 5% to 7% in the first-line baseline setting. And the Y537S as Dr. Bardia pointed out makes it more appealing to reach out for an oral SERD, which has shown to be more efficacious or with an oral SERD compared to fulvestrant, but it's particularly thought to be less efficacious.
So a very interesting case I thought, and I really appreciate the discussion. I think the million dollar discussion here also comes from the data that were just presented and published now at the annual ASCO meeting just a couple of days ago, it feels like we just came back from ASCO. SERENA-6 was presented there and we heard about this adaptive approach where we have emergence of ESR1 mutations while on first-line metastatic therapy and then we adapted based on that information to randomizing patients to getting an oral SERD and continuing the same CDK4/6 inhibitor vs continuing their AI plus CDK4/6 that they had begun their treatment with. So maybe you can talk to us about that trial a little bit and tell us what do you think about that strategy if that were to become available in clinic, how are you thinking about that strategy? Who would you apply it to? Would you apply it for all your first-line patients and do serial monitoring? If maybe you can just highlight the results and talk about that briefly, that would be helpful.
Dr. Erica Hamilton:
Sure, I'll pipe in here. I guess it depends on how long we have. I think SERENA-6 was certainly one of the most exciting and provocative trials we heard of, but also had a healthy amount of debate around it. So briefly just to outline that trial, it essentially uses the emergence of ESR1 mutations, a resistance mechanism, to tell us who we may switch from AI and CDK over to camizestrant, the oral SERD, with CDK. For this particular patient, this isn't going to help us. We already know that this patient has an ESR1 mutation, so I'm not thinking about it for this patient. There really was a good proof of principle: one, that we can detect these; two, that the emergence does lead to resistance and eventual progression. So on the control arm, the patients that stayed on AI with CDK had a PFS of about 9 months from that point, which honestly is pretty long.
And the patients that switched did much better 16 plus months. I think the question really gets at PFS2 and ultimately how we're impacting that patient's life. Are they going to live longer? Are we preventing something like liver mets or bone pain by switching that patient early or are we potentially kind of eating through our therapies quicker than we need to in the absence of progression? So I think fantastic proof of principles, certainly had fantastic data around camizestrant, seemed to be well tolerated in patients and definitely worked according to principle. But I don't know that we have the level of data really to tell us that we should be doing this routinely.
Dr. Komal Jhaveri:
Thank you so much for summarizing that so well. Dr. Bardia, anything to add, your thoughts about SERENA-6 and adoption and practice?
Dr. Aditya Bardia:
I fully agree from a scientific perspective and a regulatory perspective, it's a very interesting study because it essentially looks at ESR1 mutation and a therapy that's linked to that. From a clinical perspective, the challenge is “does the early switch really improve overall survival?” So the optimal design would be you get everyone to have a switch and the ones in the control arm in the second-line setting, they receive camizestrant. 100% of patients in the second line receive camizestrant and then if you show there's improvement in PFS2 or overall survival, that'll be the best proof of principle that early switch has a major impact, but we don't have that data. So it would be a bit challenging from a clinical perspective how to adopt this. But scientifically and from a reg perspective, it's a great study.
Dr. Komal Jhaveri:
Thank you so much. So key clinical takeaways from this case that I would like to highlight based on our discussion today is that ESR1 mutations are common in the metastatic setting. They occur under the selective pressure of aromatase inhibitors, but at baseline, at initiation of first-line therapy for metastatic disease, they're not as common in the order of about 5% to 7%. When we think about first-line therapy, CDK4/6 inhibitor remains an important therapy given the unprecedented benefit that we've been able to achieve, both with respect to progression-free survival and also overall survival. However, comorbidities and existing medications remain an important factor amongst others when it comes to choice of a CDK4/6 inhibitor. For instance, in this particular case, there was a concern about a cardiac history, a QTC that was at baseline for 440 and perhaps having an issue with QTC prolongation with a CDK4/6 inhibitor like ribociclib, which might make us want to choose alternative CDK4/6 inhibitors that thankfully are available to our patients.
And last but not the least, I think there are certain ESR1 mutations. We know that our oral SERDs, our novel endocrine agents perform better than our existing endocrine therapy agents, especially when there is an ESR1 mutation. But even within ESR1 mutations, particularly the Y537S seems to be the one that is perhaps not going to benefit so much from fulvestrant-based therapy, which is why we want to think about combination-based regimens like oral SERDs with the CDK4/6 inhibitors in such setting.
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.
