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, a breast medical oncologist at Memorial Sloan Kettering Cancer Center in New York, and excited to be joined today by two of my esteemed colleagues, Doctors Hamilton and Dr. Bardia. Please introduce yourselves.
Dr. Erika Hamilton:
Hi. I'm Dr. Erika Hamilton. I am 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, oncologist at UCLA Los Angeles. Looking forward to the discussion today.
Dr. Komal Jhaveri:
Thank you 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 third and final installment will focus on the second-line treatment of a patient with ER-positive, HER2-negative metastatic breast cancer whose tumor harbors mutations in ESR1 and PIK3CA genes.
So this is BK, a 64-year-old postmenopausal woman with ER-positive, HER2-negative metastatic breast cancer. She was diagnosed with de novo metastatic breast cancer and received first-line therapy with an aromatase inhibitor and a CDK4/6 inhibitor, in this case palbociclib, but after 22 months developed asymptomatic progression in the bone with three new liver lesions. ctDNA testing revealed presence of both ESR1 D538G mutations and, additionally, a mutation PIK3CA E545K, no presence of BRCA1 or 2 mutations with germline testing.
Now, our discussion today is going to assume that all options below are clinically available. Assuming that, which second-line therapy would be your preferred option for this patient? Dr. Hamilton, I'll reach out to you. Your options include fulvestrant with abemaciclib, fulvestrant with everolimus, fulvestrant with capivasertib, monotherapy elacestrant, imlunestrant with abemaciclib, and fulvestrant with alpelisib.
Dr. Erika Hamilton:
So this is tough. So first off, I think that these endocrine options are quite appropriate for this patient. This patient did well on her first-line CDK4/6. I would have hoped that she would still have endocrine sensitivity and moving on to another line of endocrine therapies appropriate for her as opposed to moving to an ADC. She has two mutations that point us down different tracks, both an ESR1 mutation as well as a PI3 alteration. PI3 alteration we know we can target both with alpelisib, which is specific to PI3, or capivasertib, which includes PI3K, AKT, and PTEN. ESR1, we certainly have interest in drugs like elacestrant or imlunestrant, oral SERDs, and then we also have the ones that kind of aren't mutation driven that could still be appropriate for her, everolimus combo or abemaciclib combo.
Really, when I see the coexistence of mutations like this, which fortunately is not often, I think this is an individualized patient decision. There's really advantages and disadvantages of both. I'm probably going to be thinking about targeting one of these alterations, and my choice sits either in the AKT/PI3 pathway or in the ESR1. On one hand, some patients say, "I think the single-agent oral SERDs are better tolerated and I want to do that. I want to spare some of the toxicities of the PI3 agents." And on the other hand, some patients say, "You know, PFS is really longer with those combinations and I want to do whatever's going to be best for my cancer and I'm going to try to manage these side effects and I want to go down that route."
I guess the one thing I would say is I have switched over to most of my patients that are eligible with a PI3 to receiving capivasertib. It is not a perfect drug, but what we do get rid of in terms of alpelisib is as much hyperglycemia, so then I can really focus on the rash and the diarrhea management without having to worry about the blood sugar as much. So I guess maybe my bias, if I had to put my stake on one of these, would be fulvestrant-capivasertib.
Dr. Komal Jhaveri:
Okay. Thank you for walking us your rationale and your thought process here. Dr. Bardia?
Dr. Aditya Bardia:
No, I agree with what Dr. Hamilton mentioned. It's good to have these options, and it's a matter of using these drugs in sequence. So say we start with an oral SERD, say elacestrant or imlunestrant, then at the time of disease progression you can use fulvestrant plus capivasertib or alpelisib, although in general, as Dr. Hamilton mentioned, we prefer capivasertib for better safety profile as compared to alpelisib.
In terms of additional data, there is additional data from the EMERALD study that a subgroup of patients who were on CDK4/6 inhibitor for at least 12 months, in that setting, if they had both ESR1 and PIK3CA mutation the efficacy of elacestrant was maintained. The median PFS was around 6 months, which initially was surprising, but potentially this speaks to the fact that patients who are on CDK4/6 inhibitors for more than 12 months and when they have disease progression like this patient, say, at 22 months, the tumor is still ER-dependent and PIK3CA is there, but probably the tumor is still ER-dependent. That's why you see efficacy from single-agent ER-targeted therapy. It'll be nice to look at combination of, say, elacestrant or imlunestrant plus capi or plus another PI3-kinase inhibitor, and I know there are ongoing trials like ELEVATE looking at that question, which would be attractive as well because then you're targeting both ESR1 and PIK3CA with the best available drugs.
Dr. Komal Jhaveri:
Yeah. No, I think fantastic. One thing that maybe I'll probably try and see what your thoughts were, what caught my attention when we heard the data from the postMONARCH trial when Dr. Kalinsky presented the data at ASCO and then published it in the JCO and then when we saw the results from the EMBER-3 trial as well with imlunestrant and abemaciclib, for both those combinations the subgroup analyses where they looked at efficacy by both ESR1 and PI3K mutations, the benefit was seen with both these combination drugs. What did you think about that subgroup analyses and how would you think about that data to apply in a case like this that might have both ESR1 and PIK3CA?
Dr. Aditya Bardia:
I can start. And it was interesting to see the results that in the double mutants or in patients who had PIK3CA mutation, you had benefit from imlunestrant single agent and then the doublet as well, so these are potential options to consider. An imlunestrant plus abemaciclib might be an attractive option for patients who have both ESR1 and PIK3CA mutations.
Dr. Komal Jhaveri:
Yeah, no, and that's what I felt too when I looked at both of those datasets. That was the common theme between both of them with consistent results in many ways and made me wonder if that's the approach we would want to do and maybe try and avoid... I think our decisions, as Dr. Hamilton was pointing out, are predominantly around what is the safest, most tolerable combination regimen that we can offer, and I feel like reaching out for a CDK4/6 inhibitor in this case in a second-line setting does seem like a reasonable approach, especially if we think that regardless of ESR1 and PIK3CA, that could be an option.
The issue that we face here is we don't have any prospective data. For instance, when we have data from the CAPItello-291 trial with capivasertib and fulvestrant, prior fulvestrant, prior SERDs, prior PI3K/AKT/mTOR inhibitors were excluded, so we don't know if we were to offer these patients elacestrant before a doublet strategy in the third-line setting, what that benefit would look like because when we looked at subgroup analyses from CAPItello-291, in the post-CDK4/6 inhibitor group, which is 69% of the patients, the median PFS there was 5.5 months. And then as you walked us through the data from the EMERALD trial, which was a subgroup of a subgroup, so patients with 12 months on a CDK or longer with ESR1 and PI3K had a median PFS of 5.45 months.
So yeah, it just makes you wonder. Yes, there is data. I don't think we have the best strategy necessarily and I think it's going to be a patient-physician decision-making process, and certainly some clinical factors: disease burden, prior response to therapy that will help us guide these therapies, but hopefully newer trials, including the evERA phase III trial that is looking at giredestrant plus everolimus in a phase III setting, or ADELA, which is looking at elacestrant plus everolimus vs elacestrant. That's focusing only on ESR1-mutant patients, but I'll be curious to see when that trial also has the PIK3CA data and how did that pan out. So I think hopefully such strategies will not make us wonder about this 15% of patients with dual mutations, but until then I think we're all going to have a patient-physician decision-making process. So thank you for walking us through that and your thought process of what you would do in clinic.
To wrap up for a clinical takeaway from this particular case, I think patients whose tumors harbor both ESR1 and PIK3CA mutations, it's truly a data-free zone when it comes to the optimal sequencing strategy of utilizing either an oral SERD first or a combination regimen with the agent targeting the PI3K/AKT/mTOR pathway. Certainly for combination regimens, we really reach out for the most safe and tolerable regimen combinations. We have some data for abemaciclib with either fulvestrant from postMONARCH or from EMBER-3 with imlunestrant that might be active in patients whose tumor harbor both ESR1 and PIK3CA, and we eagerly await data from ongoing efforts looking at combinations of these oral endocrine agents that are novel in combination with agents targeting the PI3K/AKT/mTOR pathway to really seal the deal with this answer for what do we really need to do for our patients.
But thank you so much for discussing this. I think 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 so much for joining.
