Host: Welcome, everyone, and thank you for joining us for today's Early Breast Cancer Case-Based Exchange webinar. We are pleased to have Dr. Neil Iyengar and Dr. Annalise Labatut of the Winship Cancer Institute of Emory University, who will be sharing their expertise and insights through today's discussion.
Host: As we move through the presentation, please feel free to submit questions using the Q&A function in Zoom. Our speakers will reserve time at the end of the webinar to answer your questions live. And now, it is my pleasure to introduce Dr. Neil Iyengar to begin today's program. Dr. Iyengar thank you for joining us. The floor is yours.
Dr. Neil Iyengar: Great. Okay. Well, thank you so much, Owen, for that kind introduction, and thanks to all of our participants for joining this webinar. I'm looking forward to a great discussion. We do want to make this interactive, and so please send any questions that you may have as we're going through the presentation, and we'll try to reserve some time at the end to address any comments or questions that come through.
Dr. Neil Iyengar: So as you heard, I'm a breast medical oncologist in Atlanta, and I'm really delighted to be joined by Dr. Labatut, who is one of our expert PharmDs, who's also going to provide us her perspectives on treatment in the setting of high-risk, node-positive, hormone receptor–positive, HER2-negative early breast cancer. Annalise, I don't know if you want to say any words to introduce yourself to the group?
Dr. Annalise Labatut: I thought that introduction was great. Thank you, Dr. Iyengar. I'll leave it to you.
Dr. Neil Iyengar: Perfect. Okay, great. So, let's go ahead and jump right into it. We've got a lot of material to cover in the course of the next hour or so, but a lot of exciting stuff, as the landscape of breast cancer treatment has been changing rapidly, as we all know.
Dr. Neil Iyengar: And so the goals of this webinar, as you can see on the screen here, are to describe the role of abemaciclib in the treatment of high-risk, node-positive, hormone receptor–positive, HER2-negative early breast cancer.
Dr. Neil Iyengar: And we're really going to focus here on patients with N1 grade 3 disease, which is, as we know, a subgroup of patients with elevated risk. But I think sometimes that risk might go under-recognized, and so we do want to highlight that subgroup.
Dr. Neil Iyengar: And then we'll share some solutions, and this is really where Annalise will lend her expertise in terms of managing AEs and dosing strategies so that we can really balance not only tolerability, but actually keeping our patients on treatment to ultimately improve their outcomes.
Dr. Neil Iyengar: So let's start with some data, basically, and we'll talk about identifying high-risk patients who are eligible for adjuvant CDK4/6 therapy. And I think we're now, fortunately, at a point where we have enough real-world data to address some of the experience that our community has had with this particular population here.
Dr. Neil Iyengar: And so, let's take a look at some of this data here. So, we know that obviously endocrine therapy is the foundation of adjuvant treatment for hormone receptor–positive breast cancer. And we also know, unfortunately, that our patients with high-risk features do face a high risk of recurrence and mortality from their breast cancer, even with appropriate adjuvant endocrine therapy.
Dr. Neil Iyengar: And this is, of course, particularly the case in patients with node-positive disease. And then finally, we also know that it's not just node positivity, but pathologic features and other issues can also define high risk, in addition to nodal status.
Dr. Neil Iyengar: So, when we look at the criteria that were used in monarchE, which of course was the seminal trial that led to the approval of adjuvant abemaciclib, it's essentially summarized here on the slide as N2 or N3 disease, so 4 or more positive lymph nodes, or N1 disease, which of course as a reminder is 1 to 3 positive lymph nodes with grade 3 histology.
Dr. Neil Iyengar: And so that's the important qualifier there, is really using that histology to identify patients who maybe have lower axillary nodal burden, but still have high-risk histopathology. And then of course, our patients who have large tumors regardless of their nodal burden, certainly we know those tumors that are larger than 55 centimeters pose increased risk for recurrence.
Dr. Neil Iyengar: And so it's in that population that was targeted for the adjuvant trial, for the monarchE trial, that we have seen data from registries and real-world cohorts that suggests that endocrine therapy by itself may not be sufficient for adequately reducing recurrence risk. So what I'm showing here is a real-world data study using the Flatiron Health database.
Dr. Neil Iyengar: And I'm sure by now most folks are familiar with this database, but it's really been a validated data set, a very large data set that contains electronic health records, ranging from January 2011 to June 2024, 16,000 adult patients with early breast cancer, and in this particular cohort who met the criteria, the high-risk criteria that we just reviewed for monarchE.
Dr. Neil Iyengar: And so in this large cohort, the subgroup of patients who had N1 disease and had that grade 3 histopathology or a tumor size 5 centimeters or greater, you can see there that they had an increased 5-year mortality risk as well as an increased recurrence risk when compared to lower-risk N1 disease.
Dr. Neil Iyengar: And these, I would say, are significant effect sizes. A 6.3% increase in 5-year mortality rate is really quite significant in this population, which we would consider to have curable disease. And certainly, a 14% increase in recurrence risk when compared to lower-risk N1 disease, I think really highlights that when we're thinking about our patients with 1 to 3 positive lymph nodes, we do still have to keep in mind the histology and other risk factors.
Dr. Neil Iyengar: And I think this is particularly important. One of the reasons why we want to highlight this is because we're really in an era of individualized treatment decision-making, right? So we certainly have scenarios where we're actually deescalating therapy for our patients with 1 to 3 positive lymph nodes and a low-risk genomic assay.
Dr. Neil Iyengar: But I think we have to keep in mind here that it's not just about deescalation, it really is about personalizing therapy. And so for some of our patients, like this population with N1 disease, but grade 3 histopathology or large tumors, they actually can have worse outcomes, and this is a population that would've qualified for the monarchE trial.
Dr. Neil Iyengar: It's a significant proportion of the population as well. You can see in this particular cohort, 81% of patients with N1 disease had grade 3 histopathology. And so that's kind of graphically illustrated on the bottom there. You can see the specific recurrence and mortality risk. And overall in those patients who met the monarchE criteria, the recurrence risk, the 5-year recurrence risk is really, I would say, quite high there. On the bottom there, you can see 29.1%, with the mortality risk of 18.5 or 18.4%.
Dr. Neil Iyengar: And interestingly, on the right-hand side there, when you specifically focus on the population we've been talking about, that N1 grade 3 or large tumor group, those numbers, those elevated recurrence risk and mortality risk, I would say are fairly close to the overall monarchE population here. And so I think this real-world dataset really helps to nicely illustrate that we can't forget about this population when we're thinking about who we want to target for adjuvant CDK4/6 therapy with abemaciclib.
Dr. Neil Iyengar: Here's another data set. This is from the SEER analysis. I think this was interesting too because the SEER analysis really identified grade 3 histology as the dominant driver of mortality risk in early-stage hormone receptor–positive breast cancer. And you can see here that this analysis was designed to identify what are those driving risk factors here. And ultimately, again, the effect size of histologic grade is really quite striking here.
Dr. Neil Iyengar: This is the adjusted chi-squared value here, and you can see that grade 3 really stands out in this very large population of over 200,000 patients from the SEER data set as association with mortality risk in early breast cancer. I mean, you can see that a lot of these traditional factors are associated as well, but I think it really puts into context; take a look at patients with 4 or more axillary nodes or patients with stage 3B early-stage breast cancer.
Dr. Neil Iyengar: I think we traditionally think of those groups as really high-risk groups, but I think it's really remarkable that it's really the grade 3 histology here that's popping out as the highest risk driver here. And so again, it helps us to keep in mind that in this era where we're using all kinds of fancy genomic platforms and tools and so forth to risk-stratify our patients, sometimes we have to go back to the basics like grade and histopathology. So, we'll talk about the risk or the role of CDK4/6 inhibitors in high-risk breast cancer. And I think this is where, Annalise, I'm going to transfer it over to you to take the virtual podium, if you will.
Dr. Annalise Labatut: Thanks so much, Dr. Iyengar. There are 2 CDK4/6 inhibitors that are FDA approved for adjuvant use in the hormone receptor–positive, HER2-negative early breast cancer space, both abemaciclib and ribociclib. Abemaciclib was approved in 2021 based on the results of the phase 3 monarchE trial. It's approved in the adjuvant setting for patients who are node-positive and with a high risk of recurrence.
Dr. Annalise Labatut: And then based on the results of the phase 3 NATALEE trial, there's adjuvant ribociclib approved a few years later, approved in combination with an aromatase inhibitor for patients with stage II or stage III early-stage breast cancer. But notably, the NATALEE trial did include node-negative patients and did not have a sub-analysis dedicated to N1 or grade 3 disease, in advance of the slide.
Dr. Annalise Labatut: Looking at some more real-world data of where are the gaps. Although adjuvant abemaciclib has been available for some time now, this high-risk patient population remains at risk in real-world practice. Another Flatiron analysis from 2023 to 2024 assessed real-world utilization of adjuvant abemaciclib, and 69% of patients who met the criteria for high risk per monarchE did not receive adjuvant abemaciclib.
Dr. Annalise Labatut: 74% of those patients had grade 3 disease. And as Dr. Iyengar mentioned, this is a high-risk patient population. And of note, the analysis was conducted prior to the approval of ribociclib. But this data, to me, indicates a need for greater education about risk, both across our practicing sides and with the patient so we can implement optimal therapy to best reduce the risk of recurrence and improve outcomes.
Dr. Annalise Labatut: There's Dr. Iyengar. Oh, actually it's me. I'm sorry. I want to introduce our first patient case, a 43-year-old premenopausal female who has T2N1 hormone receptor–positive invasive ductal carcinoma. This is a patient who I feel like is a great example for so many patients that we see in practices. She's a young mother with 2 young children. She works as a schoolteacher, and her social history and comorbidities are fairly minimal, just hypertension. She consumes 2 glasses of wine per week, a never-smoker, and no recreational drug use.
Dr. Annalise Labatut: She additionally presented with a palpable lump and suspicious findings on her diagnostic mammogram. After biopsy, it was revealed that she had invasive ductal carcinoma, high-grade, grade 3, strongly estrogen receptor–positive, CR-positive, HER21+, and a tumor size of 2.9 centimeters. Some additional surgical history. She did have a right partial mastectomy. Her Oncotype score was 26. And because of these features, after her mastectomy, she initiated treatment with adjuvant TC, 4 cycles of docetaxel and cyclophosphamide, and then completed radiation.
Dr. Annalise Labatut: Okay, so we're going to talk about what we did for treatment. Knowing her history, she had 2 positive lymph nodes, a tumor size of 2.9 centimeters, and was grade 3. And with our first polling question, "What treatment option would you recommend initiating in this patient? A, tamoxifen, B, letrozole with ovarian suppression, C, letrozole ovarian suppression and abemaciclib, or D, tamoxifen and abemaciclib?"
Dr. Annalise Labatut: Okay. Seeing a lot of letrozole, ovarian suppression and abemaciclib, and tamoxifen and abemaciclib. I think these are both great choices to consider. We'll talk a little bit more about that. We initiated this patient on ovarian suppression, and after she completed her adjuvant radiation letrozole, followed by abemaciclib at the standard starting dose of 150 milligrams twice a day.
Dr. Annalise Labatut: Abemaciclib can be given with tamoxifen or an aromatase inhibitor. About 30% of the patients on monarchE were on tamoxifen, but considering the results of the SOFT and TEXT trial, and her being premenopausal with high risk, we did opt for ovarian suppression in combination with an aromatase inhibitor. The standard duration here for the abemaciclib is for 2 years. All right, Dr. Neil Iyengar, I believe it's back to you.
Dr. Neil Iyengar: Yes, that's right. Okay, so thank you, Annalise, for walking us through that case, and I think that illustrates a case that we often see in clinic. And so now we'll go through some of the evidence from monarchE just as a reminder. Again, I think most folks are familiar with the monarchE trial here, but I think there are some key nuances and key points that are helpful for us in our clinical decision-making that I'll try to highlight here.
Dr. Neil Iyengar: So just as a reminder, here's the phase III study design here. And of course, this was patients with node-positive, HR-positive, HER2-negative early breast cancer at high risk of recurrence, and you can see essentially how it was defined here. So, as the trial was originally designed, cohort 1 included patients who had 4 or more lymph nodes, or they had 1 to 3 lymph nodes with grade 3 disease, or a large tumor size and 1 to 3 lymph nodes, a tumor size 5 centimeters or greater, as I mentioned earlier.
Dr. Neil Iyengar: Cohort 1 was the majority of patients who were enrolled on the trial. Cohort 2 were patients who had 1 to 3 positive lymph nodes and a ki-67 of 20% or greater if they didn't meet the criteria for cohort 1. But as I mentioned, the majority of patients who enrolled on the trial were in cohort 1, so we'll really focus on that cohort 1. And I just want to point out that the ki-67 of 20% or greater was later dropped from the label after the abemaciclib approval. So all the more reason really to focus on this cohort 1, which is the more common scenario anyways.
Dr. Neil Iyengar: As Annalise mentioned, it's a 2-year treatment duration, and we'll look at the landmark analysis as well as the intent-to-treat analysis which included both cohort 1 and cohort 2. And so, let's look at this cohort 1 population here and a breakdown of this population here. So about a third of patients had N1 high risk. And here, you can see consistent with the real-world data that I highlighted, nearly 70% of patients in that N1 group had grade 3 disease.
Dr. Neil Iyengar: So again, recognizing that this is a fairly common in our patients with N1 disease. And then you can see that the majority of patients, 58% fell into that group that had grade 3 disease with tumors less than 5 centimeters. There was some representation, about 11% of patients who had large tumors, 5 centimeters or greater, and grade 3 disease.
Dr. Neil Iyengar: And so now let's take a look at the efficacy endpoints here, and these are the landmark efficacy endpoints here. So this is the primary efficacy analysis, which was the 4-year invasive disease-free survival rate. That's the primary endpoint in the intent-to-treat population here. The 4-year IDFS rate was 85.5% with abemaciclib plus endocrine therapy and 78.6% with endocrine therapy alone, which was a hazard ratio of 0.65 favoring the abemaciclib and endocrine therapy arm. And of course, this was a significant difference favoring the abemaciclib arm. Therefore, the trial did meet its primary endpoint.
Dr. Neil Iyengar: Now, when we look at distant recurrence-free survival, I always like to see consistency. And so the 4-year DRFS rate is also better in the abemaciclib arm, 88.4% versus 82.5% in the endocrine therapy–alone arm, representing a hazard ratio of 0.66 favoring the abemaciclib arm. So again, this is consistent with the primary IDFS endpoint, and also I think reassuring to see an improvement in distant recurrence.
Dr. Neil Iyengar: And these improvements, these efficacy improvements were indeed durable. So here's longer-term follow-up. You can see that the 7-year IDFS rate in the cohort 1 population was 77% with abemaciclib versus 70% in the endocrine therapy alone arm, representing a hazard ratio of 0.726. And if you look on the right there, you can see that landmark analysis in the intent-to-treat population across time, noting that it's a 2-year treatment period, but you see that the curves really continue to widen.
Dr. Neil Iyengar: I mean, they start to separate at that 1-year time point, but even after abemaciclib is discontinued, you see that the curves continue to widen over time with the deltas highlighted on the top there. And I think that this is critical here, because to me, what this is highlighting is in that early stage of treatment, in that 2 years of that treatment period, what is likely happening here is elimination of the micrometastatic clone that could present trouble down the road here, and that's again, exemplified by the continued separation and widening of the deltas between the curves.
Dr. Neil Iyengar: And so ultimately there, the 7-year IDFS benefit was maintained for abemaciclib, again, highlighting that there was a 26.6% reduction in IDFS events, with a delta improvement in IDFS of 6.5% over endocrine therapy alone at 7 years. And I think really interesting and really reassuring here is what's going on with overall survival. And as we all know in hormone receptor–positive disease, 7-year overall survival is a little bit of an early look, but despite this early look, we already see separation of the curves here.
Dr. Neil Iyengar: So there, you can see in the intent-to-treat population, 86.8% 7-year overall survival rate in the abemaciclib-containing arm, versus 85% in the endocrine therapy-containing arm. That's a hazard ratio of 0.722. And there, you can see on the right-hand side there the landmark analyses again at 60, 72 and 84 months there. So again, there we can conclude that when adding abemaciclib to endocrine therapy, this leads to a 15.8% reduction in the risk of death, which is essentially exemplified by the hazard ratio.
Dr. Neil Iyengar: And again, in terms of consistency, when we look at the distant recurrence-free survival rate at 7 years, we also see a sustained reduction in distant recurrence when you add abemaciclib to endocrine therapy in this population versus endocrine therapy alone. And again, that's consistent with the IDFS benefit and ultimately the overall survival benefit as well.
Dr. Neil Iyengar: So what this translates to is when we use abemaciclib in the adjuvant setting, we have fewer patients who have to endure living with metastatic disease. And there, you can see it's 30% at 7 years, or roughly 30% at 7 years. So again, really, I think, reassuring to see these longer-term outcomes. And I would anticipate with longer-term follow-up, we're likely to continue to see benefit, if not even more accentuated benefit, particularly for overall survival.
Dr. Neil Iyengar: Let's take a look now at the safety profile. So I think, again, we were fortunate to gain experience with abemaciclib first in the metastatic setting. And so, when we have introduced it in the adjuvant setting, many of us are already familiar with the AE profile. So of course, we know that diarrhea is the most common toxicity associated with abemaciclib. In the adjuvant setting here, any-grade diarrhea was 84%, but I think fortunately, it really does tend to be early-grade or low-grade diarrhea. Only about 8% of patients had grade 3, 4 diarrhea. Fatigue and some other GI toxicities like nausea were also increased, not as much as diarrhea, but increased in the abemaciclib population here. But again, you can see that it tended to be low grade.
Dr. Neil Iyengar: And then when we take a look at hematologic toxicities on the right-hand side there, we also know that monitoring for myelosuppression, particularly white blood cell count, is important as well. We don't see as much neutropenia with abemaciclib as we do with other CDK4/6 inhibitors, but it is something that we need to watch out for. Any-grade white blood cell count decrease or leukopenia was 89%, but again, that tended to be early-grade. And when we look at neutropenia, that was 84%.
Dr. Neil Iyengar: Any-grade about 18.7% grade 3, grade 4. And again, that's lower than the grade 3, 4 rate that we typically see with similar drugs in this class. So here it's really, as I think most folks are familiar with, it's really more GI and diarrhea-related toxicity and less, but still present myelosuppression for abemaciclib when thinking about this in the context of other drugs in this class.
Dr. Neil Iyengar: Now, how did that translate to adherence? Well, on the bottom there, you can see that 19% of patients discontinued treatment due to an adverse event, and 62% had dose interruptions. So, while I would say 19% in the context of a clinical trial is an acceptable rate, it does highlight an opportunity to be more potentially vigilant about managing these toxicities so that we can keep patients on this treatment to reap that IDFS and OS benefit. And that's something we'll get into in subsequent parts of the talk here. So this will now go back to you, Annalise.
Dr. Annalise Labatut: Thanks, Dr. Iyengar. Let's revisit our patient. "What adverse event do you find the most difficult to treat for patients with node-positive, hormone receptor–positive, HER2-negative, early breast cancer with a high risk of recurrence who have initiated abemaciclib? Diarrhea, neutropenia, fatigue, or hepatotoxicity?" And of course, this is just everybody's opinion. I'll certainly share my own.
Dr. Annalise Labatut: I think that's a fair split, seeing some diarrhea, neutropenia, and fatigue. Fatigue, especially for these patients who have already received previous treatment, whether it's chemotherapy, radiation, surgery, or combination can certainly be lasting. And then the diarrhea we know can be a cumbersome side effect to management of this medication, and we'll talk about that now.
Dr. Annalise Labatut: Revisiting our patient, she did experience abdominal bloating and 2 to 3 soft to liquid stools every day when she started the medication about a week in, which really coincides with the median onset of diarrhea that we saw, which is about 6 to 8 days. Diarrhea management is a crucial part of patient education for anyone starting abemaciclib.
Dr. Annalise Labatut: Before initiating the medication, as members of the healthcare team, we really need to sit down with the patient and make sure they understand how to best utilize antidiarrheals and when they should be reaching out to us for modifications. At the first sign of any loose stool, patients should take 2 doses of loperamide, which is 4 milligrams or 2 tablets, and increase oral fluids, oral hydration.
Dr. Annalise Labatut: And from then on, patients should take loperamide with each loose stool thereafter for a maximum of 16 milligrams a day. I find that this is, in my own practice, a point that I have to drive home again and again, in that maybe patients will have this discussion, but they end up taking a dose of loperamide once a day and their diarrhea is not resolved. It really does work best with each loose stool. And then of course, when they're having persistent diarrhea, it's very easy for them to get dehydrated and feel worse when they're starting this treatment. So increasing that oral intake is very important.
Dr. Annalise Labatut: For grade 1 diarrhea, which is 4 loose stools or less a day, no dose modification is required. It's for persistent grade 2 or higher, meaning if they have 4 to 6 loose stools a day and it's not adequately relieved by loperamide, and that's when we should start looking at dose reductions and hold. We should hold until the diarrhea resolves into at least grade 1 and resuming at the next lower dose.
Dr. Annalise Labatut: Another thing I encourage patients is dietary modifications while they're having acute diarrhea. I even encourage them that knowing that we have the median onset of 7 days, that in that initial week, to avoid greasy, spicy, or heavy foods, to focus on bland foods and follow the BRAT diet. And while we normally encourage fiber-rich foods, it may be best to abstain while we're sorting out the diarrhea, or if they actively have diarrhea. Next slide.
Dr. Annalise Labatut: There are other common adverse events from abemaciclib, and the manufacturer gives us recommendations on how to manage each of them. Other common ones that Dr. Iyengar mentioned, hematologic toxicity, specifically neutropenia. Patients should get a baseline for their ANC. They should repeat labs every 2 weeks for the first 2 months on the medication, monthly for the next 2 months, and as clinically indicated thereafter.
Dr. Annalise Labatut: The moderate risk for hepatotoxicity. You can say that, that's okay, but I was just going to go through the dose reductions. We do have 3 dose levels. I am sure that we're all familiar with them. The starting dose of 150 milligrams, 100 milligrams, and then 50 milligrams twice a day. When patients can't tolerate the lowest dose, we do need to consider things like discontinuing.
Dr. Annalise Labatut: Looking back at our patient, she was able to appropriately use loperamide and her diarrhea was well controlled on it. She stopped after about 3 days on the medication and her stools were normal. We did resume on a dose reduction, and you may have noticed that she actually falls into grade 1 diarrhea with the 2 to 3 loose stools a day. This is where I really recommend taking in this personalized care model.
Dr. Annalise Labatut: This patient has 2 young children and she's a schoolteacher. She can't actively leave the classroom. And I think we have many patients in this situation, where when we're focused so much on the numbers, we might get lost in what we might actually need to do that's best for the patient. I consider if the diarrhea is in any way quality-of-life limiting, it's reasonable to consider a dose reduction. But she also was able to, once stable on the 100 milligrams twice a day, titrate back up, an approach we'll talk about later, to the full dose of 150 milligrams, and is almost done with her adjuvant therapy. She's tolerating it well.
Dr. Annalise Labatut: Let's talk a little bit more about dose reductions. In my practice, I find that many patients are hesitant to reduce their dose, fearing it might reduce the efficacy of their treatment. Thankfully, we do have data available regarding the impact of dose reductions on the efficacy of adjuvant abemaciclib. Data from a 4-year analysis of monarchE was used to evaluate dose reductions on treatment outcomes by relative dose intensity or RDI, which is the average daily dose received relative to the full dose.
Dr. Annalise Labatut: Ultimately, dose reductions did not impact invasive disease-free survival. Looking at the graphic on the left, you might see that there are slight differences here. The efficacy analysis by RDI group showed numerically higher for your invasive disease-free survival among patients who were on a lower dose or lower RDI, but the confidence intervals overlapped here, and there's no evidence to suggest a difference between efficacy across the RDI subgroups.
Dr. Annalise Labatut: And we'll see on the next slide that dose reductions improve persistence and reduce the likelihood of early discontinuation of abemaciclib. A real-world study looked at about 350 patients and found that about half of them had at least 1 dose reduction while on abemaciclib, with a median time to first dose reduction being about 2 months. And I would say that this mimics what I see in practice.
Dr. Annalise Labatut: More patients who had at least 1 dose reduction were able to continue abemaciclib at the 6-month mark compared to those who had no dose reductions, 85% compared to 64%, respectively. And the proportion of patients who discontinued due to an adverse event within the first 90 days was 4 times lower for patients who had a dose reduction compared to those remaining on the full dose. And notably, 25% of patients evaluated discontinued due to an adverse event. Among these patients, 70% of them were not dose-reduced.
Dr. Annalise Labatut: In my practice, we typically adopt a dose-escalation approach, which Dr. Iyengar will speak about. But for the patients that do start on 150 milligrams, we've begin considering that dose reduction when patients can't manage adverse events despite appropriate management strategies. For example, persistent diarrhea despite appropriate loperamide use. All right, Dr. Iyengar, I'll let you introduce our second patient.
Dr. Neil Iyengar: Yes, thank you. All right, so we'll go through a second case here. This is a case of a 68-year-old post-menopausal female who had T3N1 disease. So here's her history here. She's married and has 3 adult children. She's retired, no alcohol consumption, never-smoker, uses THC nightly. Her comorbidities, not terrible, hypertension, hyperlipidemia, some anxiety.
Dr. Neil Iyengar: So she comes in with a new right breast mass, which she palpated about 6 months ago. Her mammogram and ultrasound show architectural distortion in that area of the right breast, as well as an enlarged axillary lymph node. So she undergoes a core biopsy which yields grade 3 invasive ductal carcinoma. She's hormone receptor–positive, ER at 88% and PR at 40%, HER2-null. And she has a fine needle aspiration of the abnormal axillary lymph node, which also yields invasive carcinoma consistent with the primary.
Dr. Neil Iyengar: And so she undergoes right mastectomy and sentinel lymph node biopsy, which as I mentioned, yields T3 and 1 disease. Histology shows grade 3 disease, and she has a high-risk genomic score, Oncotype DX score of 29. So she does get chemotherapy in the adjuvant setting with 4 cycles of TC. And so let's talk about now that she has completed her surgical therapy and her chemotherapy, let's talk about how we would approach this 68-year-old next.
Dr. Neil Iyengar: So, first a polling question here to get a sense of how you all would treat her. "What treatment option would you recommend at this point for this patient? Giredestrant, letrozole, letrozole plus abemaciclib, or tamoxifen?" And let's assume that all of these treatment options are available to you. Okay. Wow, we've got consensus. I always like to see that. So, everyone voted for letrozole and abemaciclib. I think that certainly makes sense here in this patient who has high-risk disease, as we've been discussing.
Dr. Neil Iyengar: And so now, she is 68. She's functional, so I wouldn't necessarily withhold treatment from her. And this was a real patient that we treated, and so I will say that she did voice some trepidation when we discussed the AE profile of abemaciclib, particularly the diarrhea. So it was sort of a stepwise fashion here. We started her on letrozole, and as we heard from Annalise, there are dose-escalation approaches. And so that's indeed what we used here.
Dr. Neil Iyengar: After we gave her about a month to adjust to the letrozole, started her on low-dose abemaciclib at 50 milligrams BID. This was then escalated as she continued to tolerate it. So she did very well on 50 BID, had no adverse effects. We brought her up to 100 milligrams BID, and she's currently on that. We have talked with her and she does expect to further escalate to 150 milligrams if she continues to tolerate this treatment well. She's been on this dose of 100 BID for 4 months.
Dr. Neil Iyengar: I will say she is a little reluctant to increase her dose just because everything is going so well right now. But I think it is reasonable, especially given the high-risk disease, to bring her up to the 150. And of course, we can always bring it back down if necessary. And so I think this case exemplifies that dose-escalation schema that we were talking about earlier and that we'll review in greater detail now.
Dr. Neil Iyengar: And so we actually have data to support this approach. And this was the Phase II TRADE Study. And I think this is important here because it really demonstrated that the majority of patients, 70%, were able to reach that 150 milligram dose and maintain it for up to 12 weeks, at least during the study period. And so, here you can see the study design here. Patients were started on 50 milligrams BID for the first 2 weeks, and then they were escalated to 100 milligrams BID for the subsequent 2 weeks, and then escalated to the full dose of 150 milligrams for the remaining 2-year treatment duration.
Dr. Neil Iyengar: So, definitely a bit different than the case that I just illustrated, in that the patient really wanted to stick with the 100 milligram dose for a bit longer to make sure that she tolerates it, which she is tolerating it very well. So we are encouraging her to increase to the 150. So, I just wanted to be clear that the dose-escalation schema here is really an every-2-week dose escalation. And you can see in the swimmer's plot on the right there, the per patient analysis in terms of those who got up to the full 150, which was the majority of patients, as I mentioned, with some annotation for those patients who had to discontinue early.
Dr. Neil Iyengar: And what you can see in some of those patients on the bottom there who struggled was that most of them, actually, didn't even reach the full 150. So there are some patients, luckily it's a minority of patients, who just will struggle with this therapy. And so again, I think it is good to identify that at a lower dose rather than a higher dose. And you can even see 1 patient who did make it up to the 150 and then had to discontinue. And so that, luckily, is not common.
Dr. Neil Iyengar: And so this dose-escalation schema does appear to be helpful. And this actually exceeded the hypothesized estimate for the number of patients who would be able to reach that full dose. And again, I think that when this trial was being designed, based on the data that Annalise reviewed, the feeling was that if patients need to stay on the lower dose from an efficacy standpoint, that would be okay. But I think we were pleasantly surprised to see that, actually, more patients than anticipated were able to make it to that full dose.
Dr. Neil Iyengar: And so again, I think what this highlights here, putting it all together, is that we can use dose-escalation and dose-reduction strategies to really personalize and individualize our treatment approach for our patients with high-risk disease. And this really does help to keep patients on treatment and thereby improve their long-term outcomes here. And that's really what the second bullet point is getting to here, is that obviously we want to effectively manage their adverse effects, and it tends to typically be the diarrhea.
Dr. Neil Iyengar: Of course, neutropenia can happen as well, so we need to monitor for that, and use treatment holds and dose modification to address neutropenia if needed. In my practice, that's been much less common, but taking a stepwise approach or dose-escalation approach to the diarrhea has been really helpful. In fact, I would go so far as to say for me in my clinical practice, it's actually been a game-changer.
Dr. Neil Iyengar: I was rubbed the wrong way when I first started using abemaciclib in the adjuvant setting, I will say, because I was getting a lot of patients with diarrhea. But when I switched to the dose-escalation schema, I now use that routinely for, I would say, all of my patients that I'm starting on abemaciclib. It has really made tolerability a lot better, and for the majority of patients as well.
Dr. Neil Iyengar: So, I would encourage anybody who maybe has had a bad experience starting right out of the gate with full-dose abemaciclib to give the dose-escalation approach a try. And it's really, at least in my experience, has made quite a difference. And the trial data, the phase II trial data supports that as well, in addition to the real-world studies for feasibility that we've reviewed as well.
Dr. Neil Iyengar: What I think is also exciting on the horizon is that, of course, we all know that MRD testing is no longer the future. It's live and available to patients who want it. We don't quite know yet what to do with it. And so, there are trials underway that are looking at treatment escalation and deescalation approaches based on MRD. I think the tricky part right now is, especially for the monarchE high-risk patients, as I showed you in the efficacy data, the whole goal is to eliminate early on that high-risk or potentially treatment-resistant subclonal population upfront, and then that translates to long-term benefit.
Dr. Neil Iyengar: And so I'm not really using a biomarker-driven approach, apart from the histology and everything that we reviewed at this time, but there are studies underway to try to address that. I think one of the questions that come up is that are there subsets of patients in whom we should actually be using a longer duration? And what if patients are persistently MRD-positive? We don't have any data right now to suggest that we should be using a longer duration, but I think down the road we'll start to see whether or not there are successful strategies for our patients who are persistently MRD-positive and trying to prevent the development of frank metastasis. So more exciting data to come.
Dr. Neil Iyengar: And I think ultimately the adjuvant space, I mean really all of breast cancer, as we all know, is evolving so rapidly. And so, because this is ER-positive disease, we do want to see even longer-term follow-up data. So as the data continue to mature, we will see that data coming down the pipeline here and how that translates to long-term reduction in recurrence risk, which we're already seeing with the 7-year follow-up data. But of course, now the adjuvant space is changing with the availability of other endocrine therapy options to target ESR1 mutations or even starting right off the bat with something like giredestrant, for example.
Dr. Neil Iyengar: But of course, that was tested as monotherapy. So there are ongoing trials right now that are looking at combination strategies with the novel endocrine agents as well. So again, lots going on in this space. But for now, we've got very robust long-term follow-up data from monarchE, which really positions this as the standard of care.
Dr. Neil Iyengar: And so with that, we have some time left for questions and answers, and I did see some Q&A coming in through the chat here, so that's really great. Please keep them coming. I will start off with a couple of the questions here. So, the first question that we got was whether or not that 7-year survival data has changed the way that we discuss the risk-benefit profile of abemaciclib with patients. I think that in this high-risk population, I've always been very cautious in my discussions with patients because I think we've all seen, unfortunately, those patients who have late recurrences, especially in the high-risk group. In fact, some of them are not late recurrences. They're what you would expect. They're within 10 years.
Dr. Neil Iyengar: And so this is a population of patients who I do warn that while endocrine therapy is very effective, I can't predict who are the patients that are going to have that recurrence. And even a 7-year recurrence, a 10-year recurrence, I think for many patients, that is in their minds, a late recurrence, even though we all kind of are bracing ourselves for the long run. And so what this data, this longer-term follow-up data has really been helpful with is now it provides some reassurance.
Dr. Neil Iyengar: What I mean by that is that I used to have to tell patients, one of the common questions that I think we all get is, "When am I in the clear? When am I cured? When can I use that word?" And unfortunately with ER-positive disease, we know that there can be a long lag time. And so, we've had to have that difficult conversation with patients to say, "Well, live your life as if you're cured, but this can recur later on."
Dr. Neil Iyengar: But now, instead of putting a period there and ending the conversation there, we can now come back and say, "Well, we have some long-term data that adding this medication, abemaciclib, can improve those long-term outcomes and even further reduce your risk of a recurrence that far down the road." And so it has, I think, in a way, helped to provide more reassurance in those conversations. I don't know, Annalise, have you seen in your conversations, how has that longer-term data impacted your discussions?
Dr. Annalise Labatut: I think patients have found it encouraging. Keeping in mind everything that you said, that we still have a longer window of time to consider. But with each update, I find that it gives the patients confidence and improves the discussion. And patients who are maybe on the fence may be more interested in trying therapy with the new data as it continues to update.
Dr. Neil Iyengar: That's a good way to put it. Yeah, absolutely. For our patients who are on the fence, I think that helps to definitely get people over that hump. We got another question about, "What has been the most effective strategy for helping patients stay on therapy for the full treatment course?"
Dr. Neil Iyengar: I think we reviewed that with some of the dose-modification schema. The dose escalation, as I said, I think has been a real game-changer, but also the dose reduction. And what are your thoughts, Annalise, about even dose holds if you need to take a treatment break, or any other strategies that might come to mind?
Dr. Annalise Labatut: Absolutely. When we are able to offer flexibility to patients, I think they feel very seen and heard. A lot of patients do celebratory trips around the completion of their chemotherapy, and they don't need to bring abemaciclib on their 7-day cruise if they don't have to. I think that makes them feel like they can jump back into status quo, reestablish their new normal.
Dr. Annalise Labatut: In my experience, in terms of what can really help patients stay on therapy, I think setting expectations early. We often know when this is coming, when we're going to initiate this medication, and what lifestyle changes can they make beforehand. We know that physical activity is crucial for improving fatigue, especially in combination with aromatase inhibitors. Patients can always increase their hydration. I find that that's a hard habit to break if you're not a good hydrator.
Dr. Annalise Labatut: And doing those things before they start therapy, whatever they can do to set their body up for success. And of course, we talked about antidiarrheals and how important those are, but also giving them a space to know when to reach out to us. And that's if there's fatigue that's life limiting, diarrhea that's life limiting, that we can see them not based on just numbers, but what they need to do to maintain status quo.
Dr. Neil Iyengar: Yeah, really well said. We got another question about, "What has been your real-world experience compared to the clinical trial?" I'll let you take that one first, Annalise.
Dr. Annalise Labatut: I think for the most part, my real-world experience aligns. I would say we do have patients who, well, considering the dose-escalation approach, I do have less patients come off of therapy. I do have less dose reductions with the dose-escalation approach. But in terms of frequency of side effects, I would say I see diarrhea, the incidents reported, perhaps more mild. I do see less grade 3, again, with the escalation approach now.
Dr. Neil Iyengar: Absolutely. Yeah, I agree. That's been my experience also. I think that I, I shouldn't say surprised, because we know that diarrhea is an AE associated with abemaciclib, but my experience was really quite consistent with what we were seeing on trial. But like I said, when we were going through the dose-escalation data, one of the challenges when I first started using abemaciclib, and Annalise alluded to this, is that many of these patients, because they have high-risk disease, have just come off of polychemotherapy and then their radiation.
Dr. Neil Iyengar: And so understandably, I mean, these folks are exhausted and now we're putting them on therapy that has GI toxicity. And it's not just the diarrhea, it's the abdominal bloating and the cramping that can accompany that. And so I think that that was a real challenge when I first started using it. And again, just starting off at the full dose of 150, I think that's a real challenge, especially for patients who've finished chemotherapy recently and so forth.
Dr. Neil Iyengar: And so, when I switched to that dose escalation, that, I would say, really changed my experience actually to be better than the clinical trial. And that I think was, again, a game-changer because now I've had far fewer patients who've come off therapy or who've had to deal with that kind of daily nuisance of either the diarrhea or even the abdominal bloating and cramping. I see less of that, much less of that with a dose-escalation approach as well. So this, I think, has been a successful strategy.
Dr. Neil Iyengar: I do have some patients who need to stay on the 100-milligram dose, and they're kind of teetering, where they'll have some days where they're not feeling so great, maybe not having frank diarrhea, but you just know that if you push the dose, you might push them over the edge. And so like the case that we reviewed, I think that's a really good example of that patient, she actually is doing really well with it and is not actually having abdominal issues.
Dr. Neil Iyengar: But I think she's just super nervous because she takes care of her grandkids and she's very active and she travels a lot. And so she really did not want to have to deal with the diarrhea. And so she's very happy with where she's at right now with the dosing. So I do a little bit of shared decision-making as well. And while I will continue to encourage her to try the dose escalation, I think it's reasonable if she wants to stay on that 100 BID dose. I think that's reasonable as well.
Dr. Neil Iyengar: So yeah, I would say clinical experience has been similar, if not better now with the dose-escalation approach. And that feeds into another question that we've gotten, which is we've been talking about dose escalation and dose reduction. So, "How do you choose which patients you dose-escalate for versus which patients you dose-reduce for?" I don't think it's an either/or situation. Annalise, how would you address this? How do you use both tools, escalation and dose reduction when treating patients?
Dr. Annalise Labatut: I think in terms of initiation, this is a huge part of shared decision-making, because these patients, they know they're high risk and anxiety can play a huge component of that. And in the spirit of wanting to do everything, even when sharing the dose-escalation data, they can still be uncomfortable. I think those are situations where, although more rare, I may be more open to starting at full dose and letting them know that also if we need to reduce, we maintain efficacy. Again, just that as much data that you can share with the patient and patient-friendly language that makes them comfortable with the decision and a part of that decision, I think it's helpful.
Dr. Annalise Labatut: I think there's also an off-trade or, quote, unquote, "off-label" of starting at 100 that can be a good, "Let's see where you shake out. Should we go down or can we escalate?" And then of course, there's flexibility. If you increase the dose and the patient cannot tolerate it, you can go back down. And of course, if you start lower, you can increase. So I think having that flexibility is helpful as well.
Dr. Neil Iyengar: Yeah, absolutely. Yeah, I couldn't agree more. And I'm really glad that you highlighted the potential for starting at 100 milligrams. I've done that for some patients also. I think if you have a patient who just flew through chemo and did really well, and you're not anticipating is going to have major problem, I think it's reasonable to start at 100 and then go to 150. I would say for the vast majority of patients that I start on abemaciclib, I do start below the 150 dose, whether that's 50 or whether that's 100.
Dr. Annalise Labatut: Agree.
Dr. Neil Iyengar: Right? And then dose-escalate. But then I totally agree with the point that sometimes you need to pull back. And I actually tell patients the first few weeks, "The first month or 2 are a little bit of a trial-and- error period, where we're going to try to see what the right dose is for you. And it might mean that we'll have to pull back on the dose. We'll start low and we'll go up. And if we get to the point where it's too high for you, then we'll pull back."
Dr. Neil Iyengar: And I've found that patients really like that because it's this concept of individualized dosing rather than a one-size-fits-all dosing. So, I think that it's not an either/or whether you dose-escalate or dose-reduce, it's really finding that right dose for that patient in front of you. And that's been, I think, super helpful for keeping patients on therapy. So Annalise, any other comments on that?
Dr. Annalise Labatut: I do have one more comment. I do think there is also a lot of misinformation on the patient end about abemaciclib. We're in the era of information, not always the era of good information. Patient may do their own research, they may be scrolling on social media, or they may even see advertisements. And there have been many times I walk into the room to educate on this medication and patients will be very shut down and say, "I am not going to have diarrhea for 2 years." And then I try to encourage them that you shouldn't.
Dr. Annalise Labatut: Clearing up those misconceptions, what the average window for diarrhea is, what day-to-day should look like. And ideally, once we get through this trial-and-error period, I would like them to feel more like normal, feel more status quo, and can do the things that they enjoy. And I think clearing that up as soon as you can, I think you never know what information a patient comes in with. You can see what that baseline is and adjust accordingly.
Dr. Neil Iyengar: I love that. Yeah, setting expectations upfront, I think, is incredibly important. So great. Well, that does bring us to the top of the hour, and it looks like we've gotten through all of the questions.
Dr. Neil Iyengar: So I want to thank everyone for joining us today, and thank everyone also for the really excellent questions and discussions that we were able to have at the end of the webinar this evening.
Dr. Neil Iyengar: I want to thank Dr. Labatut for joining us as well and really lending her insights, because I think really taking a multidisciplinary approach also helps to optimize patient care. So with that, we'll conclude for the evening. Thanks, everyone, and have a good night.
Dr. Annalise Labatut: Thank you, everyone.
