Listen to oncology pharmacists, Julia L. Ziegengeist, PharmD, BCOP, and Rodney Hunter, PharmD, BCOP, discuss assumptions about adjuvant CDK4/6 inhibitor use in high-risk HR+/HER2- early breast cancer, providing their experiences using these therapies for their patients with early-stage breast cancer.
In this episode, oncology pharmacists Julia L. Ziegengeist, PharmD, BCOP, and Rodney Hunter, PharmD, BCOP, explore and challenge common assumptions about adjuvant CDK4/6 inhibitor use in high-risk HR+/HER2- early breast cancer, offering insights on patient selection, trial nuances, toxicity management, and real-world decision-making.
Presenters:
Rodney Hunter, PharmD, BCOP
Director of Clinical Services
Memorial Hermann Texas Medical Center
Clinical Pharmacy Specialist
University of Texas Health Memorial Hermann Cancer Center
Professor
Texas Southern University College of Pharmacy and Health Sciences
Clinical Adjunct Professor
McGovern Medical School
Houston, Texas
Julia L. Ziegengeist, PharmD, BCOP
Clinical Pharmacist Specialist, Breast Medical Oncology
Levine Cancer, Atrium Health
Charlotte, North Carolina
Link to full program:
https://bit.ly/46SPGlU
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This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Myth vs Medicine: Pharmacist’s Perspective on Adjuvant CDK4/6 Inhibitor Optimization
Rodney Hunter: Okay. Wanted to start this robust conversation about CDK4/6 inhibitors and how we really discuss their interchangeability and adjuvant setting of early-stage breast cancer, some of the main things between abemaciclib and ribociclib, and how we, as practitioners, choose these patients and what is the correct eligibility criteria.
I wanted to go ahead and bounce it off to Julia on how you feel about that. What are your thoughts when you encounter these conversations in clinical practice?
Julia Ziegengeist (Levine Cancer, Atrium Health): Only two of our three CDK4/6 inhibitors are approved in this setting: abemaciclib based on monarchE and NATALEE with ribociclib. While it could be true that we use this blanket statement that these are both used for high-risk population patients, those risk factors to qualify them for use are very distinctly different. We, as pharmacists, can definitely play a role in determining that eligibility.
To summarize abemaciclib, if you have four or more positive lymph nodes, you qualify; or if it is one to three, you do need an additional risk factor, something like a larger tumor greater than or equal to five centimeters or grade 3 disease. Notably, Ki-67 was previously listed in the eligibility criteria but has since been removed. I know some institutions get those, some do not.
With ribociclib, we are looking at stage IIb or stage III patients qualifying; or if you are stage IIa with no positive lymph nodes, you do need an additional risk factor, something like grade 3 disease. Or if you are grade 2, you need a high genomic profiling criteria, so something like an Oncotype DX or that Ki-67.
Obviously, we will talk about that in more detail when we discuss this together at HOPA. But those are complicated risk factors.
It is important to note that there is no distinction made for this to be like pathologic staging. So pharmacists can also assist in determining by also looking at their clinical staging as well. There is some things that you probably have also seen in practice that make these a little bit more distinct.
Obviously, abemaciclib is dosed at the metastatic breast cancer dosing at 150 milligrams twice daily and was given for two years based on the monarchE trial. In contrast, ribociclib is dosed at 400 milligrams. You will note that that is lower than the metastatic 600 milligram dosing given on that three on, one off setting also for three years. So a little bit longer.
Some other distinct things about these trials. They both did utilize invasive disease-free survival as their primary endpoint with overall survival as secondary. We also have to keep in mind some of those other things related to the drugs, too. Ribociclib does require a QTc cut-off in order to qualify for it. We are also going to be paying close attention to some of those things like drug-drug interactions, because this can act as a CYP3A4 inhibitor.
Rodney Hunter: Yes. I was just going to chime in as we continue to discuss this place in therapy and really nailing down this patient population when you start talking about lymph node status, and really the fact that when you really look closely into the NATALEE trial, how there were some node-negative, high-risk patients that were included in that trial, which was not identical to the monarchE trial, which was limited to patients who were node-positive. That is always a big piece when we start talking about how we are evaluating these patients that are going to be chosen for the respective adjuvant treatments.
I also think that there is a big piece of two years versus three years and patient compliance and how diligent we have to be as clinical pharmacists a lot of times on the teams to stay on those patients to keep them going throughout their treatment for the appropriate duration, to get the efficacy that we really would like to see as a clinical team.
Julia Ziegengeist: Exactly. Your point to the node-negative patients is something that is very distinct between the trials. Of course, that limits us in our ability to make any comparisons between the two, because obviously we know if you are lymph node-negative, then you are less likely to have a recurrence. When we are interpreting that data, we definitely cannot make any head-to-head comparisons. Certainly following these data as they continue to have longer term readouts, it is something to keep under consideration.
It is also interesting to note that we are seeing these iDFS curves continuing to diverge over time. We have our most updated readout, seven years for abemaciclib and five years for NATALEE and we are continuing to see those improvements. I do not know how you frame this to patients. I would be interested to hear that they are not only having a benefit while they are receiving the drug, but also even after they discontinue it.
Rodney Hunter: Yes, 100% agree. When patients are starting on the treatments, I always like to actually extract some of the information from the clinical trials, really focused on benefits so that they can see actual numbers, can see what is the why behind why we are wanting to prescribe this for them in the first place. That is always a great segway to get patient buy in to actually stay on the treatment and to be diligent.
Of course, we will talk a little bit more about side effect and adverse effect profile. But great communication between patients and the clinical team in general is always a key to success. When you think about the CDK4/6 inhibitors, if we can get in front of those toxicities, a lot of times we are much more successful at treating them for the entire duration.
The placement of these category one recommendations in places like NCCN in this early-stage breast cancer space for the CDK4/6 inhibitors, specifically with the ribociclib. Now, of course, we will talk about the overall survival benefit that you have in that particular patient population with the monarchE. But the NCCN guidelines has gotten ahead of a lot of things when it comes to what they would recommend you offer for patients in these clinical scenarios.
Julia Ziegengeist: Definitely. You make a great point related to the fact that both NCCN and ASCO have integrated these drugs into their guidelines, and I mentioned the iDFS readouts that have most recently come out five years for NATALEE and seven years for abemaciclib. Part of that data was also overall survival with abemaciclib, which was an absolute improvement of 1.8%. It was statistically significant, but it is the first time that we have seen an overall survival benefit to either of these drugs, and it is still pending for ribociclib, given the duration of treatment that overall survival benefit the guidelines have reflected that.
We definitely want to keep in mind patients’ considerations and specific factors. If a patient qualifies for both drugs, what are some of the things that you are thinking about, Rodney, in order to determine which one we want to go with?
Rodney Hunter: Yes, that is a great conversation for us to have. I feel like that is going to be the focus of what we are going to be doing at HOPA, as well as here on the podcast. Because when you do have patients that essentially tie from a clinical perspective where they do qualify for both – this is describing my clinical practice – you really start to look at the medications the patient is on currently to assess for drug interactions.
I always like to take a look back to see what did their neoadjuvant and adjuvant treatment look like in the first place to see if they really struggle with neutropenia, or they were having a lot of gastrointestinal toxicities during the adjuvant or neoadjuvant chemotherapy portion of their treatment.
Those are the two places I look at. I want to look at drug interactions. I want to look at tolerability of the previous intravenous chemotherapy that the patient received.
Then finally, a lot of insurance companies may have a CDK4/6 inhibitor that is preferred on their list, if there is going to be financial toxicity or it is going to be very challenging for the patient to receive one of the CDK4/6 inhibitors in the adjuvant setting. We do have a choice. Maybe they have four lymph nodes that are positive, have grade 3 disease, and they just fit the high-risk profile for monarchE and the NATALEE trial, then I will narrow it down to actually looking at what is their insurance coverage, to see what is best for the patient financially.
Julia Ziegengeist: Those are really great points and also a great segway into our topic of some toxicity management considerations in a lot of other settings in breast cancer. For example, with like our aromatase inhibitors, we take the approach where if you do not tolerate one, we can just switch to another.
Barring any of those considerations for high-risk factors in qualifying for the drugs, is that an approach that you generally take, and why or why not with this class of medications?
Rodney Hunter: Yes. I am always careful with these because there are nuances in the adjuvant setting. The problem we sometimes have is the way these drugs were approved initially. They were all approved in the metastatic setting. You can even include palbociclib in that conversation. But specifically with abemaciclib or ribociclib, there are a lot of similarities when you look at their label FDA wise in the metastatic setting. So toxicity and switching the patient and even some of the data we now have with things like postMONARCH, there is data showing that you can consecutively use them and still get benefit.
In the adjuvant setting, all of those types of questions have not been answered in reference to shifting CDK4/6 inhibitors in the middle of adjuvant treatment and still maintaining efficacy, maintaining which direction would you go with if you started ribociclib and you needed to switch to abemaciclib? All of those things have not been fully elucidated. We are always careful to really follow the trial to the letter in the adjuvant setting, unless it is just completely unavoidable.
When we do have those conversations where we do have an unavoidable space that we are in and we do have to switch, it usually is always going to be driven majority of the time by toxicity. That extrapolating some of the toxicities that you saw in the metastatic setting with these two drugs to the adjuvant setting, that is where you see some consistency. You do have expectations of they have a more gastrointestinal toxicity when you talk about abemaciclib versus having more QTc prolongation when you talk about ribociclib, or when you start talking about the neutropenia profile of both drugs. While both abemaciclib and ribociclib would have some amount of neutropenia, depending on the patient treated, if there is a way to address the neutropenia with growth factors, for instance, in those patients on ribociclib who have a week break, or if we want to maybe use a strategy of holding a few days of the dose when you talk about abemaciclib in that same type of patient population.
Those are all places where I feel like we, as clinical pharmacists, can really interject ourselves when it comes to addressing some of these toxicities, which outside of fatigue, are really the top reasons why patients would actually discontinue therapy with ribociclib or abemaciclib.
Julia Ziegengeist: Absolutely. I am consistently seeing that in practice as well. We also have to keep the full picture of the patient in mind when we are educating and starting them on these drugs. Because a CDK4/6 inhibitor may have been a surprise for them. Not every patient is told about that upfront, and some patients may see being presented with this option as a stumbling block, while others might see it as more of like an opportunity to prevent recurrence.
If we can educate them on those side effects upfront, knowing that they just finished chemotherapy, they probably had radiation and they are probably looking forward to resuming some semblance of their life. Meanwhile, we are telling them, “Oh, now you are going to have significant diarrhea with abemaciclib, or you are going to have to come in for these repeated labs with ribociclib.”
If we can educate them early on how to manage some of these side effects, then we are probably going to get a better buy-in from the patient as well.
What are some of those management strategies that you see most effective for abemaciclib with the diarrhea or anything with ribociclib that you think helps get ahead of these things?
Rodney Hunter: Yes, I will start off actually with ribociclib on this one. What we are commonly seeing and would not be something that jumps out when you look at the actual numbers from the NATALEE trial. Nausea and vomiting typically is something that our patients consistently will actually report to us that particular gastrointestinal toxicity. We always are going to send them home with some supportive care when it comes to nausea and vomiting.
Of course, on the top of the list is neutropenia from our perspective. We do have pre-emptive conversations with patients about, of course, getting their labs drawn every two weeks for the first two cycles. As we establish that baseline of what their neutropenia is going to look like long term, we will see if we need to employ things like dose reductions or even looking at growth factor, which is something which was allowed in the trials, but it is also something that we use clinically across the board for patients on ribociclib and all CDK4/6 inhibitors honestly in our clinical practice.
Setting the patient up to understand that that is a possibility I find it is always an easier conversation than not talking to them about the respective toxicity, and then having to backtrack and have a conversation with them when they are having the actual adverse effect. It is always a tougher conversation because they are starting to wonder, like, why were not they prompted for that when we first started the treatment?
When talking about abemaciclib, bowel regimen, of course, is always at the top of the list, with diarrhea occurring almost up to 90% of the patients. That diarrhea with the loperamide being the major control mechanism for diarrhea outside of dose reductions always are key. Most of the diarrhea showing up within the first three cycles of treatment.
Within that first three months is where I always talk to patients about being in that zone where we do not really know what dose the patient is going to be on. Is it going to be 150 milligrams twice a day, or we are going to have to drop them down to 100 milligrams twice a day? All of those conversations happen up front to make sure we establish a very good baseline for what the patient is going to expect from the adverse effects.
Yes, with abemaciclib, making sure the patient understands when we expect the diarrhea. What do we need to do as far as labs are concerned? Because, of course, the neutropenia still can happen up to 46% of patients. So it is not like it is not there, compared to ribociclib, may not be as pronounced, but certainly is something that patients may have to get their dose adjusted, hold the dose.
All of those toxicities, and I mentioned fatigue earlier is that third wheel, if you will, as far as stopping patients from continuing treatment. That is actually the big one. They are always wondering what medication can we give? Of course, keeping their nutrition up, keeping their activity up. I always focus actually on exercise. I talk to patients about if they have mobility to keep their exercise consistent as that is one of those really effective things to combat fatigue outside of trying to address it with medications.
It truly is something that if they can control that, sometimes that is the main reason why patients will end up having to get off treatment because they are just consistently fatigued.
Julia Ziegengeist: We do have the benefit of these medications having been approved in the metastatic setting for some time. We have plenty of experience with them. It is really, as you stated, a matter of reviewing with patients what they can expect, how to contact us and reach out early if these things are happening so that we can get ahead of them, rather than chasing a side effect that has been happening for some time and arming them with some of those things upfront.
Occasionally, we will get to a point where a dosing reduction is our next step. Some things to review related to that. In the monarchE trial, it was common for patients to require a dosing reduction, but less than 10% actually needed to discontinue despite this.
When we look at the NATALEE trial, they actually dosed their initial dosing at 400 milligrams, which of course was less than the metastatic breast cancer 600 milligrams. They extrapolated and justified this based on some metastatic breast cancer trials that showed that the response was similar at a reduced dose. This was used as a strategy to lessen some of these side effects upfront in this population.
When we look at the monarchE and the NATALEE trial, patients who required a dosing reduction and those that did not, these patients still demonstrated a similar level of benefit to those who maintained that full dose. It is also something to keep in mind that we want to help manage these side effects from a quality of life standpoint as early and effectively as possible, but it is not worth pushing the patient too hard to maintain these doses if we are not able to manage those side effects and have them end up discontinuing the drug rather than staying on it even at a reduced dose.
We want to try to maintain that dosing if we can, but we do still see that benefit regardless, and as I stated before, keeping that full picture of the patient in mind.
What are some of your thoughts related to that, or maybe some instances where patients were hesitant to reduce the dose?
Rodney Hunter: Yes, it is a great point. As the data was released to show that maintaining efficacy was actually not directly related to the dose. It is always something that I try to come out of the gate talking to patients about when I initially give them their education on starting the CDK4/6 inhibitor.
I like to open the lines of communication with myself and our clinical nursing staff to make sure the patient knows to report side effects to us, so that we know when we need to hold the dose and possibly reduce the dose if the patient does not respond appropriately to the supportive care that we give, and the fact that the efficacy is maintained even though the dose is reduced.
It causes patients, I feel like, to increase their communication with us as the clinical team, which can cause us to better treat the patient.
When I look at the conversations are going on across the country about do you start a patient on the reduced dose initially and then progressively go up on the dose to see if you get a tolerable dose by escalating the dose versus the current FDA approved way to dose all of the CDK4/6 inhibitors to start with full dose. Then if you need to reduce, then you reduce the dose.
I can tell you that clinical practitioners across the country are sometimes starting at a reduced dose, which the NATALEE trial highlighted the fact that that was being done at a rate where they felt comfortable even starting the trial out at the middle dosing level, as opposed to the 600 milligrams, which was studied across the board in the metastatic setting daily three weeks on, one week off.
My feeling is always we evaluate the patient to see what we clinically feel their tolerability is. We will typically start at the 150 milligrams. But there are patients, for instance, in the abemaciclib group that we would actually start them at a reduced dose and see how they tolerate and progress the dose forward, if needed.
This is, once again, something clinically see as appropriate and something that they are doing studies on. There is some data actually out there about starting at the reduced dose and seeing how it affects some efficacy, with no compelling differences with the dose reduction.
The last thing I would say specifically about this concept when we talk about the abemaciclib and the ribociclib is really talking about when you are so aggressive or rigid with your adherence to starting out to the letter with the trial, I feel like the patient is sometimes the one that actually ends up discontinuing therapy because you have been too aggressive.
I do err on the side of talking to the patient about tolerability, dose escalation when I feel it is appropriate, and also just making sure, once again, that we open those lines of communication and we have this data behind us that really show that even though the doses are reduced, the continuation of the therapy at a lower dose shows that that is going to give you that efficacy versus, of course, discontinuing the treatment is always our last resort and what we would try to avoid at all costs.
Julia Ziegengeist: Exactly. You make a good point that we are still looking at the data that is being used and strategies that are being used in the metastatic setting to try and handle some of these side effects, things like the dosing escalations and how we can apply or extrapolate those to this setting as well knowing that our goal here, of course, is recurrence risk benefit, and obviously hoping that that translates to reduced recurrence risk for distant recurrence as well.
A lot of benefit that we are potentially seeing related to this. I am excited to review all of these things in more detail as we get to HOPA and dive even deeper into each of these topics. It will be a really good discussion.