Dr. Kevin Kalinsky:
Welcome to The ASCO Post Roundtable Series on Targeting Endocrine Resistance in Hormone Receptor–Positive, HER2-Negative Metastatic Breast Cancer. I’m Dr. Kevin Kalinsky, I'm Professor of Medicine at Winship Cancer Institute in Atlanta, Georgia. Joining me today are two of my colleagues, Dr. Bhave, Dr. O'Regan. Dr. Bhave, would you like to introduce yourself?
Dr. Manali Bhave:
Sure. Hello. Thanks so much for having me today. My name is Manali Bhave. I'm a breast medical oncologist at Emory University in Atlanta and Medical Director of the Phase I Unit, and I look forward to the conversation.
Dr. Kalinsky:
Great. Dr. O'Regan?
Dr. Ruth O'Regan:
Yeah. Hi, Ruth O'Regan. Thank you, again, so much for having me. I'm Professor of Medicine and a breast oncologist at the University of Rochester in New York.
Dr. Kalinsky:
Great. We're excited to have both of you here. Today we're going to be discussing the role of endocrine resistance in hormone receptor–positive, HER2-negative breast cancer with three patient case studies. Our first installment we will focus on the treatment of metastatic hormone receptor–positive, HER2-negative ESR1-mutated breast cancer after progression on a CDK4/6 inhibitor and endocrine therapy. Let's dive in.
Case one. Linda is a 42-year-old premenopausal healthy female who's diagnosed with a right breast invasive ductal carcinoma grade II. It is strongly ER-positive at 95%, PR-positive at 80%, and is HER2 0. No prior breast imaging until it was T3N2 staging. She was noted to have both bone and lung metastasis, and that lung biopsy confirmed metastatic disease. She has an excellent performance status. She has moderate back pain from metastasis, and her hereditary genetic testing revealed no pathogenic variants.
She undergoes a TAH/BSO. She receives ribociclib plus an aromatase inhibitor, and after 34 months on therapy she develops progressive disease. She undergoes ctDNA testing and biomarker testing, which reveals a pathogenic ESR1 Y537S mutation. When we think about the next therapy, I’m curious, what therapy would you recommend next? Alpelisib plus fulvestrant, chemotherapy, capivasertib plus fulvestrant, elacestrant, switch the CDK4/6 inhibitor and AI combination, trastuzumab deruxtecan or sacituzumab govitecan? Dr. Bhave, I'll start with you. In this particular circumstance, what would you think about as your next step treatment?
Dr. Bhave:
Yeah, thanks, Kevin. That's an excellent question and a situation that we commonly address in the clinic. The patient fortunately had a very nice response to first-line CDK4/6 inhibitor and AI for approximately 34 months, which is reassuring and really suggests that she remains sensitive to endocrine therapies.
It's nice that we have the genomic information for her as well. Her genomic testing is indicative of an acquired ESR1 mutation, which predicts resistance to the AI and can be seen in about a third of patients with prior exposure to AIs in the metastatic setting. This is a little less in women that received adjuvant AI, closer to about 5%. Knowing that information is helpful, so we can consider a few options.
Historically, our recommendation used to be to proceed with single-agent endocrine therapy with our really only available SERD at that time, which was intramuscular fulvestrant. Unfortunately, we see very limited activity with single-agent fulvestrant after progression on a CDK4/6 inhibitor and AI. And now with the approval of elacestrant earlier in 2023, we know that patients with an acquired ESR1 mutation who have progressed on at least one line of endocrine therapy are now candidates for elacestrant, and elacestrant per the EMERALD study actually showed a progression-free survival advantage. This is particularly true in patients who remain endocrine sensitive, with a marker of endocrine sensitivity being response and sustained response to first-line CDK4/6 inhibitors.
And so in patients such as our patient here who had a nice response to first-line CDK4/6 inhibitor for over 12 months, hers closer to about 34 months, we actually saw a progression-free survival of approximately 8 months with elacestrant. For that reason, my next best option for her would be elacestrant as a single agent. Just of note, there was another option on there about switching a CDK4/6 inhibitor as well as switching to potentially an alternative endocrine agent. We're still awaiting on the phase III data for use of a second-line CDK4/6 inhibitor after progression on first-line CDK4/6 inhibitor with a switch in endocrine partner. However, there was some early data with the MAINTAIN study that suggests that this may be an option for our patients down the road as well.
Dr. Kalinsky:
That was a great interpretation. I think you threw out a lot of really salient points, one just about the rates of ESR1 mutations. We see across various studies that, front-line, that rate is low, like 5% or less, but then for subsequent lines it could be about a third to 40%. Also, the comment that you made about the subgroup data that Virginia Kaklamani had presented at San Antonio in 2021, that the patients who are on their CDK4/6 inhibitor for at least 12 months seem to be the ones that really seemed to benefit, where you saw that delta meeting PFS being about 6 months comparing elacestrant to physician endocrine therapy choice.
And so, Dr. O'Regan, curious about your utilization of elacestrant, whether you think about utilizing it only in patients who were on their CDK4/6 inhibitor for at least 12 months, because in the prescribing information that's not embedded in there, but I'm curious whether you utilize that. I'm also curious about the side effects from elacestrant, both what's been reported and then your own experience with elacestrant.
Dr. O'Regan:
Yeah, I think we have to remember that the analysis that was presented in San Antonio was a subset analysis, it wasn't a planned analysis. But nonetheless, I do think it was intriguing and it makes a lot of sense because the longer somebody's on first-line treatment, we know they do better with second-line endocrine therapy. So I do think, out the choices here, elacestrant makes the most sense to me.
Looking at some of the other choices here, obviously there's no evidence of AKT alterations or PIK3CA mutation, so agents that target that pathway wouldn't be a great option here. I agree about the switch in the CDK4/6 inhibitor would be an option. We probably wouldn't go to ADCs at this point.
To answer your question, overall, I think it's pretty well tolerated. There's some GI toxicity that's been reported. I haven't noted a huge issue with that in my patient population. So overall, I think it's well tolerated and it has the nice advantage of not having to be given intramuscularly like fulvestrant.
I think the other point I'd make here is that even though initially we thought that fulvestrant was potentially effective in patients whose tumors have ESR1 mutations, it really doesn't appear to be very effective at all. And if you look at the studies that we have including EMERALD, the median progression-free survival is really very short with this drug. As we know, there's a number of these oral SERDs in development and they're also being used in earlier stages including in the adjuvant setting, but also in the first-line metastatic setting with CDK4/6 inhibitors. So I think that's going to be really interesting data to see because you would expect that they're going to be at least as good as the endocrine agents that we've used up to this.
Dr. Kalinsky:
Yeah, I think you raise several good points, including just the fact that post-CDK4/6 inhibition, when we see fulvestrant as a single agent, whether it's the VERONICA study or EMERALD or MAINTAIN, we see that median PFS with single-agent fulvestrant is short. It's 2 to 3 months. And so, Dr. Bhave, are there circumstances where you are utilizing, because Dr. O'Regan had brought up this patient didn't have co-altering mutations, but let's say the patient did have a co-altering mutation such as a PIK3CA mutation, do you ever give elacestrant in combination with another targeted therapy? There are other studies like ELEVATE which are ongoing that are looking at safety and efficacy. But are there circumstances where you've used a combination or are there also circumstances where you're concerned about utilizing single-agent elacestrant?
Dr. Bhave:
Yeah. I have not used elacestrant in combination with another targeted agent, like a PIK3 inhibitor, as yet. I'm waiting for some of the data for that. But I would say in patients that have co-mutations, which have come up, I think you have to look at the patient's overall performance status, their co-morbidities, the toxicity differences, but perhaps in a patient who I felt had a PIK3 mutation, which, in general, translates to some endocrine resistance, and if they had a shorter duration of response to first-line CDK4/6 inhibitor, then in that patient, if they had, again, co-mutations with PIK3 and ESR1, I might be more likely to choose a PIK3 inhibitor in combination with fulvestrant compared to a elacestrant. And then perhaps down the road, depending on their response to that, I might consider single-agent endocrine therapies.
In terms of who I might consider single-agent endocrine therapy vs combination strategies, I think, again, it comes down to the general gestalt about that patient. What was their pace of disease? What is their tolerability for combination strategies vs single-agent activity? Other comorbidities, so if they have perhaps hyperglycemia or metabolic-type comorbidities, then I would have some concern about the use of agents like alpelisib. And so, I think we're lucky to have so many options for patients who have progressed on first-line CDK4/6 inhibitors and AI, and it's still the art of medicine in deciding what would be the right next option.
Dr. O'Regan:
I think the other agent not to forget about is everolimus, because I do think its activity in particularly endocrine refractory disease, when you look at those studies, both BOLERO and then TAMRAD, they were quite marked, impressive hazard ratios for using everolimus. Obviously you don't need to have any alteration of the mTOR pathway. There's no predictive biomarkers. So I do think that's another option for patients.
Dr. Kalinsky:
Yeah. If this particular patient received elacestrant and then, let's say, is on for 6 months or so and then has some mild progression, let's just say you repeated liquid biopsy and did not detect any additional mutations beyond an ESR1 mutation. Ruth, what therapy would you think about at that time? Would that be like a fulvestrant/everolimus? Would that be tamoxifen plus everolimus? Do you have a go-to in that sort of circumstance?
Dr. O'Regan:
It obviously depends on what they received previously, but I think, thankfully, everolimus has data with pretty much all of the endocrine agents. We always forget about tamoxifen, I think. So that keeps it as an oral regimen, but fulvestrant also with everolimus would be an option for a patient like that. But also something like capecitabine, I think, which then obviously would allow you to use antibody-drug conjugates afterwards.
Dr. Kalinsky:
Yeah.
Dr. Bhave:
Also important to note that particularly with everolimus, we do have some data on lowering the dose of everolimus and maintaining efficacy while making it more tolerable. So in some cases, I actually consider starting at a lower dose to help with that tolerability.
Dr. Kalinsky:
Yeah. I think, also, the other thing about everolimus when it first came out was we weren't utilizing the prophylactic oral dexamethasone or steroid rinse based upon the SWISH study, and so that has really made a notable difference just in terms of tolerability.
Dr. O'Regan:
Yeah, I agree with you. I routinely use that, but I think comparing it to something like alpelisib, it's a much easier drug to give. But obviously the data from SOLAR, that also had very impressive results.
Dr. Kalinsky:
Yeah. I think the other thing just to mention before we conclude is just how many endocrine-targeted therapies are in development. We've been talking about SERDs, but there are selective estrogen receptor modulators that are in development like lasofoxifene, a randomized phase III trial for patients with ESR1 mutations. We have complete estrogen receptor antagonists, PROTACs. I suspect, in the next few years we'll see a number of agents that could increase the armamentarium of drugs to target the estrogen receptor.
I think that the key clinical takeaways from this particular case is, we've talked about some of the advances in hormone receptor–positive, HER2-negative disease. We've talked about the post CDK4/6 inhibitor setting. We've talked about some of the limited activity with single-agent fulvestrant. We've also talked about single-agent elacestrant with those with some durable responses on their prior CDK4/6 inhibitors, and this is approved for patients with ESR1 mutations. We're awaiting studies beyond phase II trials, phase III trials of CDK4/6 inhibitor plus switching endocrine the after progression on CDK4/6 inhibition, such as post-MONARCH, and then we also mentioned that there are novel endocrine therapies that are in development.
This brings us to the end of this case. Please see the other segments for further discussion about the latest research in breast cancer or visit ascopost.com. Thanks so much.
