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Precision in Practice: Navigating AE Mitigation in the Era of Targeted Treatments to Elevate Clinical Outcomes for Patients With High-Risk HR+/HER2- Breast Cancer

Fundamentals I: Optimizing Adjuvant Therapy in Patients With High-Risk HR+/HER2- Early Breast Cancer

All right, and that brings us to our first session here, where I am going to focus on optimizing adjuvant therapy and high-risk hormone receptor-positive/HER2-negative early-stage breast cancer.

What Is “high-risk” in HR+/HER2- EBC?

So for our first slide here, we are just going to talk a little bit about what deems a patient high-risk, especially in the early breast cancer setting. To the right here, we have a few risk factors, such as endocrine therapy resistance. Do they have a large tumor? How many lymph nodes do they have? As well as what is the grade of their cancer? Also, we consider their Ki-67 proliferation rate. Do they have lower ER/PR levels? So, is this behaving more like a triple-negative breast cancer? And then also considering, is it luminal B, HER2-enriched or a basal-like molecular subtype?

Looking at this graph, this shows an annual hazard rate of occurrence by stage. So stage I, II, and III. And so, we see with stage III, it peaks around years 2-3, but never really drops back down to zero. And so, this is really truly the fundamental challenge that we see with hormone receptor-positive disease, and that, there is really never a safe window. For instance, with triple-negative breast cancer, we know that recurrences usually happen within the first 2-3 years. A little different because of the long history and persistent tail of recurrences is just longer with our hormone receptor-positive patients.

Risk of Distant Recurrence After 5 Yr of Endocrine Therapy

Again, looking at this meta-analysis, this is also going to give us some good information here. This study looked at ER-positive breast cancer diagnosed in 1976 to 2011. Patients had received five years of endocrine therapy and were disease-free at five years. Now, I am going to walk you through the 20-year distant recurrence risk for these patients. It is categorized based on nodal status.

We have patients who are node-negative, patients who had 1-3 nodes, and then patients who had 4-9 nodes.

So looking at that 20-year distant recurrence risk for patients who had no node involvement, it was 22%. If they had 1-3 nodes, it was 31%. And then if they had 4-9 nodes, it was 52%. This tells us that more than half of these patients with 4-9 nodes will eventually develop metastatic disease. And so, when we let that information sink in, these numbers are fairly high for these patients.

Again, a key message here, there is really no safe window. I reiterate that because these patients can recur at 10 years, they can recur at 15 years, they can recur at 20 years. So it is very important that we are doing all that we can upfront.

I will draw your attention to the box at the bottom here just looking at the diagnosis after 2000, the 20-year risk is about a third lower. That reflects the improvements in the treatments that we have for these patients over time.

Adjuvant EBC Trials With CDK4/6 Inhibitors

Quickly here, just looking at some of the trials that have looked at CDK4/6 inhibitors in the adjuvant space, PENELOPE-B and PALLAS looked at palbociclib, not going to spend a lot of time there.

These trials were not successful, but we do know that monarchE, our monarchE data, as well as our NATALEE data, we have seen great benefits from these studies. And so, I am going to focus primarily on our monarchE with abemaciclib, which focused on high-risk, node-positive patients. And then our palbociclib that opened the window a little bit more to include a greater population here for our high-risk patients.

monarchE: Adjuvant Abemaciclib + ET in High-Risk Node-Positive, HR+/HER2- EBC

Focusing a little bit here on our monarchE data, looking quickly at the study design, this was a Phase III open-label study. It included about 5,600 patients. Patients had high-risk, node-positive disease. They could have received prior chemotherapy. They were pre or post-menopausal, did not have any distant metastatic disease. It must have been randomized within 16 months of their surgery date.

It had two different cohorts. Cohort one included the majority of patients here. These were patients with four or more positive nodes, or they could have had 1-3 nodes plus a grade 3 disease or a tumor size that was 5 cm or greater.

Cohort two only included about 9% of patients. And these were patients with 1-3 positive nodes, Ki-67 of 20% or greater. These are your lower-grade tumors, smaller tumors here. They were randomized to the treatment arm of abemaciclib 150 mg twice a day for up to two years. This was paired with endocrine therapy, and this was compared to endocrine therapy alone.

Our primary endpoint was invasive disease-free survival. And then here we also have our key secondary endpoints. I am not going to read them all. I do want to highlight OS in this category as well, because we will talk about that for the monarchE study.

monarchE: iDFS and DRFS in ITT

So, monarchE has an extended follow-up period, which is great because it has given us a lot of data. We see that the invasive disease-free survival as well as the distance recurrence-free survival is pretty consistent across the board. We see benefit across all the subgroups.

I am going to focus on our most recent data with the seven-year invasive disease-free survival. We saw 77.4% in our abemaciclib arm compared to 70.9% in endocrine therapy alone, showing us a 6.5% absolute benefit. When we look at our disease risk-free survival, we see in our abema arm 80% compared to 74.9%, yielding a 5.1% absolute benefit. And so with having all of this follow-up data, we do see that this study has a carryover effect.

When patients stopped abemaciclib at two years, they kept benefiting from taking the therapy for that two-year period. It is not highlighted here, but at the three-year mark, the absolute benefit was 5%. At five years, 6.6%. And then of course, as I just mentioned, at seven years, it was 6.5%. If we plotted this on a graph, we would see that the curves do not converge, but they continue to separate as time goes on. And so, that is definitely something that we want to highlight when we are talking to our patients about starting on these therapies.

Regarding patients with any recurrent event on both arms, distant recurrence was the most common type of relapse. We see in our Abema arm, it was about 13.6%. Endocrine therapy alone was 18.5%.

monarchE: OS in ITT (Key Secondary Endpoint)

And then this slide, I think a lot of people were excited about getting information on OS. Again, this study had a great deal of follow-up. And so, this is a recent reveal of monarchE showing OS.

So the hazard ratio here, well, first I will start with the percentages, but our OS percentage for our abemaciclib arm was 86.8% compared to 85%. And that was an absolute difference of about 1.8%. The hazard ratio was 0.84, yielding a 15.8% reduction in the risk of death with the abemaciclib plus endocrine therapy. And while 1.8 sounds fairly modest, we have to contextualize these findings. We know that this is, again, a two-year treatment producing benefit for five years after stopping. And then, of course, fewer patients in the Abema arm are living with metastatic disease, so that is great. And then, of course, many future deaths in the control arm have not actually happened yet. What we will likely see over time is that this absolute difference will continue to increase with more follow-up.

monarchE: Safety

Quickly looking at our safety data for monarchE, our headline toxicity is diarrhea. When you are seeing these patients, that is top of the list, things that you are going to discuss with them. It accounted for about 84% in any grade for patients on study. It is manageable with loperamide and diet modification. Usually peaks around the first month, a couple of months that the patient starts.

Other AEs to be aware of is neutropenia at 46%, fatigue at 41%, and then, nausea at 30%. Dose adjustments were common on this study. There were about 62 dose holds, 44% dose reductions. Discontinuations were 18.5%. A thing to highlight is that there were only 8.9% discontinuations after a dose reduction. That will also be something that is important, and we will talk about it as we progress through the slide.

Many patients in a clinical setting, right, and even in the study, will usually stop before you optimize their dose. So making sure that patients are on a good, solid dose. I guess you could say a sweet spot, right, where symptoms are tolerated well, is important early on for us to keep people on therapy for the two-year duration.

NATALEE: Adjuvant Ribociclib + ET in Intermediate- to High-Risk HR+/HER2- EBC

All right, switching gears here now, we are going to focus on NATALEE data, which was a Phase III open-label study.

It included about 5,100 patients. This is a broader population. It included your stage IIA through III. Patients could have been pre- or postmenopausal. Chemotherapy was permitted as well prior to this study, as well. Just to walk you through the different stages here, if they were stage IIA, again, they could have had node-negative, grade 2 with a Ki-67 of 20 or higher, or had a high-risk genomic risk profiling. Again, if they were N0 with grade 3 or N1. Stage IIB was an N0 or N1, and then, of course, they could have had stage III disease. This is the only CDK4/6 inhibitor trial that looks at node-negative patients. So again, broadening that window so more patients are eligible.

Patients were stratified to two different arms here. With ribociclib at 400 mg daily, and they actually take this for three weeks on, one week off. I want to put emphasis on the 400 mg dose. So that dose was intentionally decreased for better tolerance. We know that in a metastatic setting, patients actually are taking 600 mg at the highest dose.

For their non-steroidal AI, patients receive letrozole or anastrozole. And this combination was compared to endocrine therapy alone, again, with a non-steroidal AI. Primary endpoint here was invasive disease-free survival. And then, of course, we have our secondary endpoints below as well.

NATALEE: iDFS

And when looking at our invasive disease-free survival for our NATALEE data, the median follow-up here is not as long as monarchE, but we do have about 55 months of follow-up. And so with our five-year invasive disease-free survival, we saw in our Ribo arm that it was 85.5% compared to 81%, yielding a 4.5% absolute difference. This study, as I mentioned again, patients do take this for three years. And so, at the three-year mark, we saw an absolute difference of 2.7% compared to the five-year data at 4.5%. So, we are seeing a little bit of carryover in this study as well. Again, I imagine as follow-up continues, we will see that these curves continue to spread out as well.

OS is trending in a positive way. It is not yet statistically significant, but those are just some of the differences that we have seen. And of course, this study has shorter follow-up.

NATALEE: iDFS in Node-Negative Subgroup

Looking at our subgroup with our node-negative disease, again, important because these patients would not otherwise be eligible for a CDK4/6 inhibitor, but we see that our invasive disease-free survival here, the five-year mark is 90.3% compared to 84.6% in the endocrine therapy alone arm. That is showing us a 5.7% benefit there.

NATALEE: Safety

And then this is a bit of a busy slide here. I am just going to highlight a few things.

When looking at ribociclib toxicity profile, neutropenia is high on the list as one of the AEs of special interest. We see at any grade, it occurred at 62.5%. Diarrhea did occur here as well at the bottom; however, not as high as we saw with abemaciclib, it is only 14.5%.

Unique Ribo concerns, we want to watch out for those liver-related AE toxicities. They tend to usually happen a little early on, again, as we are monitoring labs. We do know that we have to monitor our QTc prolongation. So we do that upfront, and then again, we do it around 14 days of that first cycle. And then again, just noting that the 400 mg dose, again, intentional so that patients could better tolerate this therapy.

Adjuvant CDK4/6 Inhibitors Are NOT Interchangeable

All right, so we have talked about both studies, both drugs, ribociclib and abemaciclib. But I do want to put emphasis that our adjuvant CDK-4-6 inhibitors are not interchangeable. They have characteristics that are pretty distinct to both.

We talked about the criteria itself. When thinking about duration of follow-up and evidence of overall survival for these patients, we know that monarchE has a little bit more follow-up, right, compared to ribociclib. We know that we have now seen OS benefit with monarchE data in patients who qualify for both, because I feel like this happens fairly often, and really, if they are node-positive or if they have these high-risk features, you may talk to patients about both of them, but things you want to consider is that endocrine therapy backbone with ribociclib, we are using non-steroidal AIs, using that as well with abemaciclib. However, we can also pair abemaciclib with tamoxifen. Their prior treatment tolerance, right? At baseline, do they have a lot of neutropenia? Are their counts struggling? Do they have GI toxicities upfront? That might be something you would consider if your patient qualifies for both.

The duration of treatment. So two years with abemaciclib, three years with ribociclib. So, collaborating with your patient to see what would be the best fit.

And then again, just thinking about those concurrent medications, comorbidities that your patient might have. Ribociclib is associated with more drug-on-drug interactions. If you have a patient who highly likes to use supplements and they are taking a lot of medications, you might lean more towards doing abemaciclib. And again, as I mentioned, just talking about the GI toxicities, liver toxicities, your patient may have, which will help guide your decision-making when choosing a drug.

Treatment Algorithm for Adjuvant Targeted Therapy in HR+/HER2- EBC

This is just a good visual for how you can utilize an algorithm when you are thinking about how you are going to treat your patient upfront.

You are going to see if your patient has that germline BRCA mutation. If they do, then they may be getting endocrine therapy paired with olaparib for one year. I have seen this in clinic where we do olaparib upfront, and then once we have finished that year, we transition to one of the CDK4/6 inhibitors.

Drawing your attention to the right side of the screen here. If you have a patient with four or more nodes, this is your high-risk patient with node positivity. We know that they qualify for Abema, but they also qualify for ribociclib. And patients with 1-3 positive nodes, here in the middle of the screen, they have that grade 3 disease, so they have a really large tumor. Again, qualifying for both.

If they do not have as high of a grade and it is more intermediate, maybe their tumor size is a little smaller, then perhaps maybe they have a bowel comorbidity, then you are thinking about ribociclib paired with their endocrine therapy. And then of course, for node-positive lymph nodes, then we are only really thinking about Ribo in this arm, because our patients who get abemaciclib, those are your node-positive patients. So, we consider Ribo here. And then if they do not have any additional high-risk features, then considering endocrine therapy alone.

Patient-Specific Considerations

Quickly, just to review this slide, these are just patient-specific considerations.

With abemaciclib, I have highlighted a lot of these things as we have talked, and I am just going to hit the highlights here on this slide. Again, dosing for Abema is 150 mg, taking it twice a day.

So continuous dosing here. For ribociclib, 400 mg, they are taking two tablets once daily. So intermittent dosing, because they are doing three weeks on followed by one week off.

The common toxicities we talked about, highlighting that Abema is highly associated with diarrhea. Sometimes we can see elevated serum creatinine, a little neutropenia, as well as nausea. With ribociclib, we do see a good bit of that neutropenia. We can see elevated LFTs there, but not a lot of diarrhea, again, associated there.

Rare toxicities to note, pneumonitis ILD, while it is rare, it can still happen. So you do want to be monitoring your patients closely. They are both associated with VTE risk. Abema has a higher association, and then monitoring that QTc prolongation for those patients as well. I think my slides may have advanced.

With the endocrine therapy backbone, again, know that we can utilize our non-steroidal AI with both of them. Abema can be given with tamoxifen. And then just differences in the duration, two years versus three years.

Key AEs With Adjuvant CDK4/6 Inhibitors: Monitoring and Prevention

Not going to talk a lot about this slide.

I know Cierra is going to talk a lot about the monitoring and prevention of AEs, but I think this is a great visual. Again, just seeing which side effects are associated with both drugs versus one of the drugs. So with diarrhea, we can see both in both drugs.

With the AEs, again, hepatobiliary toxicity, we can see in both. Neutropenia, we see in both. It is highly associated with Ribo. VTE risk, abemaciclib. Again, if paired with tamoxifen, that risk goes up. That rare risk of ILD, pneumonitis, and then QT prolongation, again, associated highly with ribociclib.

Dose Reductions Can Maintain Benefit in Early Breast Cancer

And then, just to quickly highlight, again, the dose reductions, I think something that is very important that you talk about this upfront with your patient.

We know the evidence supports similar efficacy for Ribo and Abema in patients who require a dose reduction. I think it is good to let your patient know upfront if they are not tolerating therapy or if they are having issues, we can make adjustments.

Our goal here is to keep our patients on their full two-year duration or full three-year duration of treatment. And we would rather them do that at a lower dose than take them off. And perhaps they only complete four months at the full dose. We want to make sure we are getting them through their treatment.

NATALEE and monarchE: Tolerability and QoL

And then this is just a tolerability and quality of life overview here, highlighting the most common side effects associated with these drugs. I do want to highlight that on these studies here, the quality-of-life tools did not actually capture the more early events. So the events that happened within the first 1-3 months. So, taking this with a grain of salt only because I feel like that is where most of the side effects are usually most prominent, and that is where we are usually figuring out how we are going to dose in and keep going on treatment.

But overall, both drugs, fairly well tolerated by patients.

Skill building and Feedback I: SDM for Adjuvant CDK4/6i Therapy

All right, so this brings us to our first skill building and feedback activity. So we want to hear from you all as we work through this case study here.

Now, I am just going to read off our case study, and then we are going to talk about a few questions. So we have a 480year-old premenopausal woman with high-risk hormone receptor-positive/HER2-negative early breast cancer who presents after a lumpectomy and a sentinel lymph node biopsy. Her pathology shows ER-positive of 95%, PR 80%, HER2-negative disease.

She has a tumor size of about 2.8 cm. It is grade 3. Her Ki-67 is 35%, and she has three of the 12 axillary lymph nodes were positive from her path report. She completed dose-dense AC followed by weekly paclitaxel and adjuvant radiation and started goserelin plus letrozole which she has been on for about eight weeks. Her hypertension is well controlled, baseline QTc of 420. And she is concerned that treatment-related adverse events may interfere with her work and daily functioning.

So, a few things to note here before we jump into our questions. She is high-risk, right? She has positive nodes. Upfront, we know she qualifies for both abemaciclib and ribociclib. She is sitting across from you, and she asks, do I really need to add another drug to my therapy, and which one is going to be the best drug?

Starting with our first question here, how would you describe the rationale for adjuvant CDK4/6 inhibitor therapy to this patient? Let me just open up our question window here.

And I will also have Cierra and Kim as well chime in to give us their input as well on how they would think about this patient and explain the rationale.

Kimberly Podsada (UC-Sand Diego Moores Cancer Center): Hi, this is Kim. I think you did a tremendous job, especially those first slides of really highlighting who a high-risk patient is. And that risk of recurrence is really key to explain to our patients that we have identified this person as being high-risk, and our goal with the additional medication is to really reduce that risk of a recurrence, local recurrence, metastatic recurrence especially. So I think that is really key information for them to understand that rationale of why they are going to take a medication that may give more side effects that they have to manage, that the ultimate goal is keeping them cancer-free.

Dr. Freeman: Awesome, I agree, Kimberly. I think we have also some input here from the chat. We have one of them saying, encourage her that adding a CDK4/6 can further reduce your risk of recurrence by about 25-30% beyond what the endocrine therapy does alone in high-risk cases like yours.

Absolutely, I agree, Adrian. Very important to tie in that data, and depending on if your patient is numbers-driven, or maybe they need an analogy that helps them. I think a good one to think about is that the endocrine therapy is the lock at the door, and then we are adding an alarm system to that by adding that CDK4/6 inhibitor.

Yes, I think someone said, do we send our answers now? Yes, if you have any answers, please send them.

Yes, provide data from the trial showing the numbers that are important overall regarding survivorship. Yes, I agree. All right, I do not know if we have any more comments here.

I am going to transition us here to our second question of consideration. What key differences between adjuvant options would you discuss during shared decision-making with your patient? This is when you are having that collaborative conversation with your patient. You guys are talking about the differences in the drugs themselves, right? Thinking about duration, you know, does your patient take a lot of medications upfront? What would we consider here for these, for this question?

Kimberly Podsada: I would also want them to understand the clinical trial designs a bit also, and in a very simplified language of this trial showed patients who had lymph node positivity. So for abemaciclib, we do see that there were more patients studied who were lymph node-positive. That was the patient population versus ribociclib. The 2-3-year difference is definitely something to consider discussing. I mean, it is important. How to take the medicines. You are taking it either twice a day or you are taking it daily, three weeks on, one week off.

So really getting a sense of your patient. Do they already have baseline diarrhea? Are they already neutropenic from chemotherapy? So some of the side effect profile is important as well as what criteria did they really truly fit when it comes to looking at the two key clinical trials?

Dr. Freeman: Yes, Kim, I completely agree. I think Madison also agrees with you. She wrote in, she said that, you know, duration of therapy, two versus three years. Considerations of those comorbidities. Do they have, yes, cardiovascular disease because of the QTc prolongation for Ribo and then IBS if we are considering Abema. We have somebody else. Archana wrote in review of the AEs as well as the support available to the patient. You want to explain the trial in ways that the patient can understand so it helps them make an informed decision.

And I completely agree, Kim. We talk about the data, and I still hone in on, I think data is great, that drives our decisions, but these are opportunities also, where we want to get input from our patients so that we are making decisions together for the patient.

All right, and then lastly here, just talking about how would we counsel this patient on expected adverse events, monitoring and the role of dose adjustments. And we have hit on some of these already, but I will open the door here just to talk a little bit about how would we talk to our patient? What if we have a patient that says, there is no way I am going to be able to take a pill for two years that gives me diarrhea? How do we address this question in clinic when we have our patients in front of us?

Cierra, what do you think? I am going to get your input. You are like our AE guru.

Cierra Ryan (Winship Cancer Institute of Emory University): Yes, so I always tell people, the patient is what sits in the room, the human is what is outside. And so, basically expectations versus realities in terms of, I do not know what is going to happen. I can tell you what I think is going to happen, but until something actually does.

And so, just going over, here is what I think is going to happen, here is what is going to happen if it does. We have different dosages, we have different supportive medications, but I think it is mainly getting them to understand that we are trying to treat them as humans and making sure that they can go on about their daily life. Because again, we see this stuff all the time, but for them, it is the first time they are probably seeing it.

And so, it is what do we expect to happen, what they need to call us for, things that they can have at home on hand for these things. If she is a lawyer and has to be in court, she cannot be having crazy diarrhea. And so, how can we set her up for success? How can we monitor these things in terms of if this, then this? And probably explaining pretty early that consistency is better than the highest dose possible. And so, if we have to have fewer interruptions at a lower dose, but she can stay on it more consistently, then that is more important than getting the biggest dose there is.

Dr. Freeman: Completely agree. And I think that, as you mentioned, talking about these things upfront, sometimes the more information, the better. It leaves your patient walking away again so they can make informed decisions, but that they also know these are things that we can manage along the way, and I know I am not stuck with the highest dose, but that I can get through treatment. I mean, the two-year period, and we all know, right, as we treat our patients, we are supporting them every step of the way. And so, I think it is just very important that we put that out upfront, that there is flexibility in how we go about treating our patients with the CDK4/6 inhibitor.

So I think, I do not see any more questions here, or let me see. Yes, all of the comments I see here are aligning with a lot of the things that we have already talked about. No, we only have about three, like two, maybe one minute or so in this section, but I completely agree with all the comments that are coming in. Great information here.

I am just going to advance here, and then we are going to give it over to Kim so that she can talk about advanced disease.

Posttest 1

But before we do that here, I am going to go to our posttest question number one, since we have talked about the data.

You are talking with JL, so it is going back to our first pretest question. You are talking with JL, a 48-year-old premenopausal woman with high-race hormone receptor-positive/HER2-negative, early breast cancer, who qualifies for both adjuvant abemaciclib and ribociclib. Which of the following factors is the most important to discuss with her when individualizing her treatment plan?

And I will give you all just a second here to answer this question.

All right, so the answer is option B. And it looks like, just based on the results here, looks like we have a little bit of a mixed response.

More people did answer year two to three, and we are just going to quickly talk about why answer B is our best option here.

Baseline QTc is fine at 420. I think when we think about the impact of letrozole, we know that that can be given with both drugs. Her menopausal status, again, is not going to affect how we give the medication, which one we choose. So, option B is the best because both adjuvant options, again, appropriate. But really, we are looking at the true differences. Can our patient tolerate treatment at two years? Is that something they are willing to do? Versus do they actually want to commit to a three-year period? And then, of course, we can get into the other things that differentiate the treatments. But based on this, I would go with option B as our best answer.

Tools and Resources for CDK4/6 Inhibitor Management

And then lastly, just to wrap things up here, these are just some tools that you all can utilize.

Starting with our Decera clinical resources, we have a nursing management pocket guide that discusses monitoring schedules, dose modifications, AE management algorithms. So that can be very helpful as you are working in your clinics. They also have an interactive CDK4/6 Adverse Event Management tool that can be useful, goes through some specific patient cases.

And then lastly, just the MASCC oral agent teaching tool. It is a standardized patient education for oral anti-cancer agents. There are some assessment questions that you can utilize, education points, evaluation tools. It is available in multiple languages.

So all free, all useful, and things that you can utilize as you are treating your patients. Again, I would like to thank you for your time and engagement today.