What Advanced Practitioners Need to Know About CDK4/6 Inhibitors in HR+/HER2– Breast Cancer: Optimizing Benefit and Minimizing Toxicity

Mikel Ross:

Hello and welcome to this virtual roundtable about managing CDK4/6 inhibitors. And in particular, optimizing adherence by minimizing toxicity. My name is Mikel Ross. I’m a nurse practitioner at Memorial Sloan Kettering Cancer Center, where I support the breast medicine service. Joining me for this roundtable are two amazing colleagues. On the West Coast, we have Sarah Donahue. She has a master’s in public health. She’s a nurse practitioner working at the Carol Franc Buck Breast Cancer Center, part of the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco. And then just down the road here in New Jersey, Dr. Deborah Toppmeyer. She’s a professor of medicine at the Robert Wood Johnson Medical School, the chief medical officer, the chief of the Division of Medical Oncology, the director of the Stacy Goldstein Breast Center, all part of the Rutgers Cancer Institute in Jersey at Rutgers, the state university of New Jersey.

So as I said, we’re going to talk about CDK4/6 inhibitors and really about managing toxicity and adherence. Just to kind of couch us and all the different things that we’re looking at, here is a slide that looks at the toxicities that are the most common with each of the three agents, abemaciclib, palbociclib, and ribociclib, and also the safety and monitoring schedules we have for those.

As you look across the top, we think about diarrhea, hepatobiliary toxicity, QT prolongation, neutropenia, thrombotic events, and finally, interstitial lung disease and pneumonitis. They have within each of those what the monitoring schedule should be and what we then would go to the package insert in order to know how to manage those. Then in terms of diarrhea, we think particularly about abemaciclib optimizing anti-diarrheal therapy, making sure that patients are appropriately hydrated. Hepatobiliary toxicity, that tends to perhaps be more of a lab abnormality and in particular abemaciclib, where we see increases in serum creatinine that are not necessarily authentic changes, not part of the hepatobiliary, but a lab change. But not actually a change in kidney function, but a lab abnormality based on how the medication’s processed. But here we see that we do need to look at labs for hepato toxicity every two weeks, every two months, and that is commonly indicated for both abemaciclib and ribociclib. QT prolongation pretty much is something that is in the domain of ribociclib.

Not that it couldn’t happen with others, but it is the one of the CDK4/6 inhibitor that has a specific monitoring requirement on day 1, day 14 of the first cycle, beginning of day 2. And then, as indicated, neutropenia, all of them have a monitoring requirement in terms of thrombotic events. Abemaciclib is, when you look at the three package inserts, the one that continues to have a precaution for clotting issues. And then finally interstitial lung disease and pneumonitis, all of them can have a risk for that.

And we’ll talk a little bit moving forward about how likely are those various risks and how we look for those. The one toxicity that I wanted to spend a nice chunk of time talking about here is diarrhea and, in particular, some of the success that we have had in the clinic in extrapolating data from another anti-oncolytic neratinib that has a high rate of diarrhea. But a clinical trial that looked at how do we minimize that and we’ve extrapolated that into the clinical setting for abemaciblib and had some great success. So, what I’m specifically talking about was the control trial, and in this trial was a phase 2 trial, an international open-label phase 2 study looking at different prophylactic anti-diarrheal regimens to improve the tolerability of neratinib as recorded in the ExteNET trial. The ExteNET was the approval in metastatic breast cancer and in that trial, 40% of patients had grade 3 diarrhea and there was a 17% discontinuation rate. So, in the control trial, there were five arms. There was, how do we, Arm 1 using loperamide, also known as Imodium, in order to limit diarrhea. Arm 2, pairing loperamide with budesonide, which is a steroid. Arm 3, pairing colestipol, a bile salts sequestrant, with loperamide. Arm 4, colestipol with, as needed, loperamide. And then number 5, something as simple as starting at half dose and going up. And what were the results of that trial? Once again, taking the ExteNET as the historical control and can we make it better by implementing these prophylactic regimens? It seems like we actually can. In the ExteNET trial, there was a 17% discontinuation rate. Loperamide did not really tend to improve that discontinuation rate that well. There is still an over 30% rate of significant diarrhea and 20% of patients stopped. But then when you paired loperamide with one of the, in the case of budesonide, a steroid colestipol, a bile salt sequestrant, you had a significant drop in the discontinuation due to diarrhea, down to 8%, down to 4%, and you actually see an improvement moving away from grade 3 diarrhea and more patients experiencing grade 2, grade 1, or, in fact, no diarrhea.

And interestingly, the best strategy to stop discontinuation was to start low and then just use, as needed, Imodium. But what I would say is as a result of these trial, and this is one of these places where as a clinician I feel a little bit safer coloring outside of the line, is no, these data are done for a CDK4/6 inhibitor. And yet, with supportive care medications, I feel like we do have a lot more latitude in terms of what we can do in practice and maybe not meeting quite the strength of data that we would require for a therapeutic outcome in terms of DFS or overall survival. I have actually utilized colestipol and also the titrating up method, but in particular colestipol, to not only help with CDK4/6 diarrhea, but then also pertuzumab-related diarrhea and other agents.

So, you know, something that maybe we could, you know, share and utilize across different medications that are causing side effects. So, that’s kind of a strategy I’ve utilized based on that trial, certainly. And that’s not the totality of all the side effects we can have on CDK4/6 inhibitors. But Sarah, let me reach out to you first. What are some of the side effects that you found problematic on CDK4/6 inhibitors and what are the strategies that you’ve utilized to minimize the cost and allow people to optimize the benefit?

Sarah Donahue:

When we're discussing abemaciclib and diarrhea with that, definitely dose reductions can help, if that's required, just by a small dose. One thing that I found is that, you know, that the first dose reduction is from 150 twice a day down to 100 twice a day. But I'll use 150 at night and 100 in the morning, so that, is one what one thing that I can do. I think that dose reductions are something that we do. But before I get to that, I will often use loperamide to prevent diarrhea with patients. If they're having a lot of diarrhea at first, it's not like neratinib, it's not something where I need to start them on around the clock, loperamide, maybe not something where I necessarily with all patients be to start them on a lower dose. But it is a strategy that I've used with patients that have had like, you know, diarrhea prior to starting, issues with that in the past with prior therapies. But definitely telling the patients to start the loperamide at the first sign of diarrhea and then being in touch with them very closely for the first one to two weeks so that I can figure out how I can prevent the diarrhea. I could have them take, like, a half of a tablet, loperamide, daily to prevent the diarrhea that they would have or at bedtime. That’s one thing that I've done. Sometimes it's a whole tablet. I also talk to them about diet changes that they can make, avoiding spicy foods, fatty foods, avoiding sometimes, like, raw vegetables can make it worse, raw fruit, sort of the obvious things. But definitely sort of I think if you think about it, just trying to help the patient stay on treatment and using a lot of different strategies. Dose preventive medications, diet, lifestyle-type things. When it comes to, that's like the main side effect with the abemaciclib. When it comes to palbociclib and ribociclib, I've had patients come to me with problems with mouth sores like canker sores. And what I've done for those patients is I give them a little oral dexamethasone and I have them swish and spit. And some patients need to do it every day. Some patients just do it as soon as the canker sore appears, and then it helps it resolve very quickly. And that was something that we took from use with everolimus. We were doing that with everolimus. And so, then we've been using that now with our CDK4/6 inhibitors. I have them do salt water and baking soda rinses as well. Avoiding those spicy citrus-containing foods helps.

Mikel Ross:

Dr. Toppmeyer?

Dr. Deborah Toppmeyer:

You know, I think the data are very interesting with slowly increasing the dosing and I have done that with neratinib, where we had participated in one of the studies that, you know, looking at all the different regimens. But I think it's very effective and as I was saying before, if I'm concerned that somebody is going to have diarrhea, for example, I had a very, very young woman who was I mean, she's tiny, but she was, you know, 92 pounds at baseline and dropped to 82 pounds in, you know, all throughout her chemotherapy. She was having GI issues, so I was very, very leery about, you know, even starting her on abemaciclib and she was as well. And we started at the lower dose of 100 milligrams. And, you know, she's tolerated it very, very well. I don't think she could do it more because she's already having a few GI side effects. But I think, you know, the titration works and same thing with neratinib. The titration works well and I think, you know, as Sarah mentioned, you know, constant follow-up with patients, seeing, you know, how are you doing, you know, encouraging them to reach out on the portal to My Chart, and obviously, if they're having more significant issues, the triage nurse, etc. But I think that constant education and connection with the patient makes a huge difference.

And I think some of the pharmacies, for example, we have a specialty pharmacy, you know, that they are constantly reaching out to the patient to see how they're doing. Monitoring side effects also makes a difference. So, it's you know, it's several layers of their health-care team that are engaged in and, you know, monitoring their progress and dealing with side effects and looking at compliance. So, I think all of those issues are very important.

Mikel Ross:

And Sarah, just to join on to what you mentioned about mucositis and oral lesions, we also used rinses. But when the oral patients are limited to a singular one, we also have a standard where we can just recommend clobetasol on that single oral issue. And I just talked to people about take a Q-Tip, dab it on the one spot. Don't tell the pharmacist at Walgreens, where are you going to put it because they think you're crazy. But in fact, it works exquisitely well. And it's kind of like a targeted, once again, steroid where if you don't have a diffuse mucositis, you can really pinpoint that singular lesion.

Sarah Donahue:

Is clobetasol a solution that you’re ordering?

Mikel Ross:

Ointment.

Sarah Donahue:

Ointment.

Mikel Ross:

Ointment, yeah, just a 15-gram tube will last forever.

Dr. Deborah Toppmeyer:

I would I would just say one thing, you know, one thing that we just have to make sure is to check the patients white count if they do have a significant number of, just as a teaching point, if they have a significant number of mouth sores. You know, generally I don't get too crazy about the neutropenia on, you know, the CDK4/6 inhibitors and when patients are feeling well in particular I do follow it. I mean obviously, you know you have to use some judgment but it's not like I'm saying, oh my gosh, the ANC is a thousand, I have to do something. I'm a little bit more liberal about it on the CDK4/6 inhibitors.

Mikel Ross:

Right. But absolutely, those mouth sores are the canary in the coal mine, so to speak, because they’re the clinical presentation of what’s the lab abnormality often.

In addition to the more common side effects of diarrhea, which you talked about, the management of that, maybe titration might be a new strategy for some of us in order to avoid it. But the serious but less common side effects—embolic events and pneumonitis—I actually had to refresh myself because when these first came out, I recall middle, single-digit numbers that were reported and those are still what we’re getting in the package inserts when you look at them across the board for all the CDK4/6 inhibitors. Pneumonitis is still reported out at around 3%. And embolic events still reported out at 5%. Are these things you’re seeing? And if they are, what’s your kind of herald sign and an index of suspicion when using these agents? Sarah?

Sarah Donahue:

I’ve seen patients develop pneumonitis on ribociclib and I believe abemaciclib. I don’t have one patient in mind right now, but I’ve had more than one actually. I’ve had a handful. Definitely shortness of breath and cough are worrisome symptoms that I tell them they have to report to me in between visits. Usually on exam, everything seems normal, when I’m auscultating, I can’t tell. So I’m getting that CT chest when they have that symptom.

The patient that I’m thinking of did have pneumonitis with two in a row. We tried changing from one CDK4/6 inhibitor to another. So I would definitely be more concerned with any patient that has ever had any pneumonitis from a drug, even though we don’t necessarily have data saying that if they’ve had it with prior drugs, that they’re going to get it with this. It’s just something that I think we don’t know. I think it’s just the data desert.

But as far as the embolic events, if a patient were to complain of one leg swelling or pain in their calf, then I’d be concerned that they were having DVT and I would get a Doppler ultrasound. If somebody was complaining of shortness of breath, cough, that CT test, if they’re having pleuritic chest pain, I might be getting the CT test with contrast in protocol. So maybe with this one, I would always get it with contrast. I don’t know. Now I’m changing my mind, but it’s certainly something that can happen again. Small numbers in those trials, and I actually have not had a patient develop PE or DVT while on this in my own personal experience.

Mikel Ross:

Dr. Toppmeyer?

Dr. Deborah Toppmeyer:

One of the earliest patients that I treated developed very severe ILD and actually subsequently succumbed to complications. And you know, at the time it wasn’t a common side effect. Obviously we treated her very aggressively, but it was it was unusual. And so that was one of my first introductions. But, you know, it is a rare side of that. And actually in the time that I had been prescribing the CDK4/6, I had not seen much pneumonitis since it’s much more common with other agents, as you know. I do watch them very carefully.

I had a patient who came in today. I had switched her from interestingly palbociclib to abemaciclib because she developed a very significant increase in her liver function test, which I had not seen on palbociclib. So, we stopped it. Her liver function tests normalized very quickly. But then I started her on abemaciclib. And today, she was complaining of some shortness of breath. I have a low threshold to her. She’s going to get a non-contrast CT scan. So I think, like T-DXd, a lot of these agents, we just have to be much more proactive about earlier in diagnosis because earlier intervention certainly mitigates risk of compromise.

Mikel Ross:

And let’s throw another wrinkle into that. Think about, and I have a patient of mine, first-line investigation drug was exposed to immunotherapy, and then presents with that type of a symptom. And then you’re trying to think, is it late effect of the immune therapy? Is that what this is right now? Is it lymphangitic spread. So you know it never gets boring because we all get to be detectives every single day.

Dr. Toppmeyer, as you just mentioned, this is stage four disease. Our goal is to increase life and at the same time maintain quality. And we have to have that perspective. And so, Sarah, as you talk about taking breaks, there is nothing wrong in the middle of a marathon deciding you’re going to run mile 17 a little bit slower you know, you can do that and hydrate a little bit more.

And Dr. Toppmeyer, I don’t know if you remember, but you were actually that person that taught me to have that hat on after you have had a very long and busy rotation as inpatient attending to always keep in mind what our goals are with people, so I’ve always tried to carry that with me and always trying to share with people. Folks, it’s a marathon, not a sprint. We don’t have to drive all in every single time. We can make some of these side effects better and we don’t want to overreact to any one thing. Let’s have that conversation because in the conversation we’re going to figure out what the next best step is for you.

So with that said, I once heard that pills in a bottle don’t work, and I think that’s still true unless something has changed I don’t know about. And you know, these medications, despite being incredible, the clinical evidence of their utility, they do come along with some cost and the side effects. I really appreciate the conversation we’ve had about minimizing some of those costs so we can optimize some of those benefits and also thinking about how extrapolating what we know in terms of supportive care management from other situations to new situations can and does help and also never forgetting the basics of dose reduction as well as titration starts slow and get people where they need to go.

So with that, I want to thank you for your time. I hope that those people that tune into this as well as I have, learned something that they can take away and use to help their patients have another good therapy that’s going to optimize their outcome. So thank you again for joining us. I’d like to thank both Dr. Toppmeyer, as well as Sarah for their time their insights and their thoughts taking time out of their busy days.

For more information, please always visit JADPRO at advancedpractitioner.com and thank you so much for tuning in and taking the time to learn a little bit more about how we can get the very best for our patients.