Case 3

Dr. Matthew Goetz:

We're going to transition to the cases here in the metastatic setting. And we're going to start with a patient that I've taken care of. She's a 35-year-old female who presented with de novo stage IV metastatic breast cancer, ER-positive HER2-negative. She was in her usual state of health when she palpated a mass within her right breast. And on physical examination in mammogram, there was a 2 cm mass confirmed. She had palpable ipsilateral adenopathy. A biopsy at that time demonstrated tumor cells that were both estrogen and progesterone receptor, highly positive that is they were greater than 90% and with strong nuclear staining in HER2-negative. She did have a Ki67 that was performed. It was quite high. HER2 was negative at 1+. Now because of the extent of disease, both from a tumor standpoint as well as nodal standpoint, she did have a PET scan and did have several areas of uptake outside of the breast.

So she had disease uptake not only in the breast and adjacent lymph nodes, but also the scapula, several ribs as well as in the pelvic region. At this time, she had no obvious visceral disease. And other than the breast mass, she was asymptomatic, she didn't have any bone pain and really, rather than the psychological aspects of a newly diagnosed, life-threatening malignancy, did not have any other physical symptoms. So at this time, this was about 4 years ago, she was treated with ovarian function suppression, letrozole and palbociclib. And I thought I would just stop for a moment and think a little bit about where we've come over the past 3 or 4 years and there's a lot that's been changing in this area. Sarah this patient presented 4 years ago and let's say she presented to your clinic today, what would be your choice of therapy? Would you approach it similarly? Would you make any changes?

Dr. Sara Chumsri:

Yeah, so I think since we have these three CDK4/6 inhibitors in the clinic, we learn along the way that they're actually not quite created equally. So even though in the same class of drug, these drugs seem to have very different pharmacokinetics, the half-life of the drug and how these drugs perform in the clinic. And they do have different side effects, particularly like this patient because she's premenopausal. And now that we have not just the progression-free survival data from the MONALEESA-7 trial but also benefit with overall survival specifically in this specific group of patients who are premenopausal. So in this lady, I probably would want to go more with ribociclib in her case rather than palbociclib if I would've seen her today.

Dr. Matthew Goetz:

So you mentioned the MONALEESA-7 data. Kevin, when those data came out, did that change your practice right away or were you still thinking these CDK4/6 inhibitors are probably created equal and we can use them interchangeably or have your thoughts changed at all?

Dr. Kevin Kalinsky:

Yeah, I will say when the MONALEESA-7 data came out, I had switched to utilizing ribociclib as my preferred front-line CDK4/6 inhibitor, but exclusively in the premenopausal population because we had a study that was dedicated to that and we were seeing an OS benefit and then was seeing the PALOMA-2 OS data at ASCO in 2022. I will say those were data that I was eagerly anticipating and was awaiting and once we saw that there was not an overall survival advantage in that particular study, I would say that our preferred CDK4/6 inhibitor is ribociclib. There are of course data with abemaciclib as well, but when we're having discussions about side effects and tolerability and things like this, ribociclib tends to be the preferred agent.

Understanding that there are some drug-drug interactions, of course, you have to do those EKGs within the first several weeks; every other week for three times. So I will also say that part of the conversation from the PALOMA-2 study has been that there were more patients who had "endocrine-resistant disease," they didn't follow patients for as long as others. There was other different censoring that was going on. So this particular patient I believe presented with de novo disease, however, I would've started ribociclib for this particular patient.

Dr. Matthew Goetz:

Okay, thank you very much. And I think many of us have really moved that way as we've seen the data with not only MONALEESA-7, but of course MONALEESA-2 as well as MONALEESA-3. And we see the consistency of the survival data now both in the pre- as well as postmenopausal setting, the first- and second-line setting. I think we can really say very confidently to our patients that this drug, in this case ribociclib, has a consistent survival advantage. I'm interested, Kevin, you mentioned the EKGs. Do patients find that much of an inconvenience? Does that come up much as a problem?

Dr. Kevin Kalinsky:

I think it really is dependent on the site, right? So one of the things we experience here at Emory is that there are different sites, different setups. For some, the EKGs are done just right down the hall and then for some, it requires going to a different building and it's just a little bit more operationally challenging. So when we made the decision as a group or that we're going to make ribociclib our preferred agent, this was the conversation that we were having, was how could we do this? And there are other means, like for instance, there's Novartis, who is the manufacturer of ribociclib, has created these EKGs that you can have on hand, within the office and believe some institutions may utilize that. That's not something that we utilize within our group. I don't think that it has been a tremendous barrier for utilization of ribociclib, is just one of those logistics that's required when you're starting a patient out on ribociclib.

Dr. Matthew Goetz:

Great. And I would say from my standpoint as well, I think just letting the patient know upfront this is what it's going to be and I think generally, it's not too onerous for patients. Sara, as you've begun to perhaps transition from palbociclib to ribociclib, are you seeing any differences in the tolerability profile as you begin to prescribe more of the ribociclib say than what we have been doing of course for many years has been using palbociclib?

Dr. Sara Chumsri:

So I think when I discuss with the patient about these agents, especially with the side effects profile, I think the EKG did come up a couple times, especially that's raised the red flag. They've been on palbociclib and they did not have to do this. So I think the conversation would be actually to reassure the patient that incidence of these prolonged QTc is actually quite low, but it's just something that we have to monitor. I think most of the series is less than 1% to 2% in most of the series, but another thing that you have to take into account is medication, like drugs, that potentially interact and will prolong QTc, particularly things like ondansetron or some of the antibiotics.

So that's something that's a little bit more that you have to take into account when you discuss with the patient and also to prescribe some certain medication. But on the other hand, if we reassure the patient that the incidence rate is quite low and it's something that we just have to check and make sure, I think most patients accept the fact, especially when you have something that shows significant improvement in overall survival.

Dr. Matthew Goetz:

Okay, great. So this patient again was treated with ovarian function suppression, letrozole and palbociclib, and she had a really outstanding response. Her PET scan demonstrated a marked interval improvement of all the previously seen hypermetabolic lesions. Now as I said, this patient was asymptomatic from the start, so this improvement did not make her feel any better from a standpoint of pain, but certainly, she was very pleased being able to come in and see that improvement in the PET scan. So she remained in remission for about 14 months and then at about the 14 to 15th mark, she did have disease progression in the bones.

Again, this was seen by PET, she had multiple new lesions that developed. Again, she was asymptomatic. Kevin, in this situation, obviously, there's a lot of data that are emerging right now about the role of second-line therapy in patients that have progressed, in this case on an AI CDK4/6 inhibitor, again, palbociclib. Obviously, you've presented the MAINTAIN data and we are getting more and more data about the activity of single-agent endocrine therapy. Your thoughts on management of this patient in this situation, again, otherwise asymptomatic, several new sites of bone disease on, in this case, palbociclib plus AI OFS?

Dr. Kevin Kalinsky:

Yeah, and I think for this particular patient, we've learned a lot about the biology of single-agent fulvestrant after progression on a CDK4/6 inhibitor. One, I will say this patient progressed within 14 months of her hormonal therapy and CDK4/6 inhibitor, shy of what we see with the median PFS. And we've seen from VERONICA, from the EMERALD study, from MAINTAIN, just how the control arm does that they receive single-agent fulvestrant and it's around 2-ish months, right? And so I tend to use, outside of a clinical trial, I tend to use doublets. So one, I would check to see if this patient had a PIK3CA mutation or not, right? If she has a PIK3CA mutation, I would think about something like fulvestrant plus alpelisib.

If a patient was PI3K wild-type, then I tend to utilize fulvestrant and everolimus based upon the PrECOG study. You had mentioned MAINTAIN, which was a study that was looking post CDK4/6 of fulvestrant with or without ribociclib. It is a randomized phase II trial which showed that the doublet was better than just doing fulvestrant alone, but it was also meant to be really a proof-of-principle study. And we're seeing results of other CDK4/6 inhibitors after CDK4/6 inhibitor studies, so the story is not over and we're awaiting the results of the ongoing phase III trial of fulvestrant with or without abemaciclib, the postMONARCH study. But outside of a clinical trial, I would tend to utilize something like fulvestrant and everolimus if the patient didn't have a PIK3CA mutation.

Dr. Matthew Goetz:

Okay, fantastic. And so indeed, this particular patient did undergo NGS testing. She was actually identified while we were awaiting the results of her NGS testing, she was actually screened for a clinical trial in the context of a study called ELAINE 2, which was testing the combination of abemaciclib and lasofoxifene, which was a novel serum. So she was identified to have on CT DNA testing the Y537S ESR1 mutation and therefore, she was eligible to enroll in this phase II clinical trial, testing the combination of abemaciclib and lasofoxifene. This particular patient, it was quite interesting because she had a fantastic response, I mean, just absolutely fantastic, and she's actually now approaching the end of year 2 being on this study with this particular combination.

Now as it turns out, we actually did get the results of her NGS testing shortly after of course she was screened for the trial and she was identified to have a PIK3CA mutation. And so of course, in this situation, we have that as an option. And had we not treated her on a clinical trial, certainly, treatment with alpelisib would be considered a standard approach.

Sara, question for you. So, these patients who undergo NGS testing, obviously right now, we have one drug, alpelisib, which is FDA-approved, but oftentimes, we get some of these additional mutations that seem like we might be able to target them, but then we're not really quite sure. So the idea of an ESR1 mutation in this situation, would that effect in any way how you would treat her off study?

Dr. Sara Chumsri:

Yeah. So that's a great question. I think now that we do more and more NGS, we learn more about the ESR1 mutation. So even though it's rare in the de novo metastatic setting, in neoadjuvant setting, less than 1%, we see this more and more upon disease progression after aromatase inhibitors, some study incidences can go up as high as 47%, 48%, almost half of the patient would carry this ESR1 mutation and the Y537S and D538G are one of the most common one, which are the mutation in the ligand binding domain and that stabilize the estrogen receptor and make it be able to signal despite not having the estrogen around. So this is some of the common mutations that we see and that emerging data that perhaps this mutation would confer a sensitivity to other types of endocrine therapy rather than aromatase inhibitor.

Things like SERMs like lasofoxifene that you put this particular patient on; some of the new SERDs, like fulvestrant or elacestrant, hopefully that may be approved later on. So I think if I have one of these patients who started to have ESR1 mutation, you can consider some of those agents, and the data that we saw in the PADA-1 study that reported previously that if you see these emerging mutation and perhaps switching them with the endocrine therapy, but continue on the CDK4/6 inhibitor they might have a longer progression-free survival. So, something to be considered and discuss with the patient some of the clinical trials that are already ongoing.

Dr. Matthew Goetz:

Great, thank you. And actually, in reality, I failed to mention here, I got ahead of myself, I was so excited about the findings on how she did with the abemaciclib and lasofoxifene, actually failed to mention that after progressing on the AI palbociclib regimen, she actually did get single-agent fulvestrant and had stable disease for 4 months followed by disease progression in her liver. So she had progression both in her liver and bones when she went on to the clinical study. Okay, thank you very much.

I think this particular case illustrates a number of issues and I think one of the things that is so exciting right now is I think Kevin, as you mentioned, we're moving beyond, well, single-agent hormonal therapy post-CDK4/6, I think we've been there, done that. And I think interestingly, what we're seeing of course is that single-agent hormonal therapy really has very limited activity in this post-CDK4/6 space. And I think if we look at the data from the elacestrant, EMERALD trial, there may be a subset of patients that do get some prolonged benefit, but I don't think we know quite who they are as of yet. Your thoughts on that, Kevin?

Dr. Kevin Kalinsky:

Yeah, I think when you do the landmark analysis or if you look at the patients who may be on even at 12 months, for instance, there is a population of patients. Also say in the EMERALD study with looking at elacestrant, numerically, there were more patients who are on that oral SERD compared to fulvestrant. So, there are patients who may have some durability to their stability of their disease or their response, but we can’t, as you said, identify who they are.

Dr. Matthew Goetz:

Okay, great.