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

Mikel Ross:

Welcome to this virtual roundtable about managing CDK4/6 inhibitors in hormone-receptor, HER-2 negative and, in this case, metastatic breast cancer. This is a case-based approach, and my name is Mikel Ross. I'm a nurse practitioner at Memorial Sloan Kettering Cancer Center where I support the breast medicine service.

I'm absolutely delighted to have with me two amazing colleagues. First of all, we have Dr. Deborah Toppmeyer, Professor of Medicine at the Robert Wood Johnson School of Medicine. She is the chief medical officer, the chief of the division of medical oncology, and the director of the Stacy Goldstein Breast Cancer Center at the Rutgers Cancer Institute in New Jersey, part of Rutgers, the state university of New Jersey. Then leaping all the way to the West Coast, we have Sara Donahue, master’s in public health, nurse practitioner. She practices at the Carol Franc Buck Breast Cancer Center, the Helen Diller Family Comprehensive Cancer Center, part of the University of California, San Francisco.

As I said, we are here to talk about CDK4/6 inhibitors, their role in the management of metastatic breast cancer, and Dr. Toppmeyer will take us through a grounding in the data and then we will move on to a discussion on how to optimize these therapies for patients.

Dr. Deborah Toppmeyer:

Thank you, Mikel. Absolute pleasure to be here with you and Sarah. I'm briefly going to review the role of CDK4/6 inhibitors in metastatic breast cancer. As you know, we have made extraordinary progress over the past actually 2 decades in terms of a much more targeted approach to the treatment of breast cancer. This has actually resulted in metastatic breast cancer prevalence actually increasing. Women are living longer with metastatic disease. Unfortunately, still about 40,000 women died per year of metastatic disease, but the number of women living with metastatic disease has really increased, and that is because of better therapies and better weapons to fight the disease, including this incredibly important class of agents, the CDK4/6 inhibitors.

As you know, there are several agents that have been approved in the metastatic setting including palbociclib, ribociclib, abemaciclib, and there have been several studies that have confirmed their utility in the metastatic setting. I think what was remarkable when these original studies first came out, including the PALOMA-2, the MONALEESA-2, which was in post-menopausal patients first line with either palbociclib or in MONALEESA-2, ribociclib, MONARCH-3, abemaciclib, in again frontline metastatic disease versus ribociclib in MONALEESA-7 in women who were pre- or perimenopausal who received AI and TAM plus goserelin.

What was remarkable was really the progression-free survival across the board was extremely similar, with a hazard ratio of ranging from 0.53 to 0.56, with on average a 10-month difference in terms of progression-free survival. Again, you see these numbers here, 0.56, 0.57, 0.54, 0.55. To me, that was what was a remarkable finding, but it's really important to understand that we can't really do cross-study comparisons. All of these trials enroll a slightly different group of patients, even if the eligibility criteria were quite similar.

I think one of the areas that there has been some question is that when you look at the MONALEESA data, both MONALEESA-2 and MONALEESA-7, that there appears to be an overall survival advantage. In MONARCH-3, there is a trend, and those data are still maturing. However, with PALOMA-2, there did not appear to be a survival benefit, with a hazard ratio of 0.96, but one needs to be careful that this was the secondary endpoint. There were also several issues regarding follow-up, particularly on the placebo control trial of hormonal therapy alone, so drawing any conclusions to say that palbociclib is not effective compared to the other agents, I don't think it is a fair comparison.

I'll come back to that a little bit later in the context of other trials that have been done. When we look at second line, similarly to first line, the PALOMA-3, MONALEESA-3, MONARCH 2, all of these agents in combination of second line with a CDK4/6 inhibitor once again showed remarkably similar findings in terms of progression-free survival with hazard ratios ranging from 0.50 to 0.59 in the MONALEESA trial. Once again, in terms of overall survival advantage, it certainly favors ribociclib and abemaciclib as well.

Mikel Ross:

Thank you, Dr. Toppmeyer. I appreciate that. We have been so fortunate since 2015 when palbociclib first had the market or entered the market to really be able to utilize this medication, and just the tremendous difference it has made. I've not been doing this terribly long, since 2012, but I remember before then we recycled aromatase inhibitors and thought that maybe that would help before we got people onto infusional IV, and what a difference it's been in just the last 5 to 7 years. However, time does add up. What I would say or ask is since these agents did become available, all 3 of them within the 2-year period of 2015 to 2017, have you seen a difference in terms of how you would utilize these agents, what you might start with, what you feel patients tolerate, better or worse, just any evolution since they were all out and available? Sarah?

Sarah Donahue:

I think when palbociclib was first approved, we started using palbociclib. I was familiar with it at my institution because we did some of the trials that got the approval, so I felt really comfortable with managing the side effects and it was easier for me. Then when ribociclib became approved, I was very skeptical of trying something new. I'll admit, the idea of getting EKGs made me a little nervous. Would I be able to actually get them in the timely manner the baseline, 2 weeks and 4 weeks? Could I actually operationalize that? Then with the approval of abemaciclib, just concerned more about the diarrhea and how patients would tolerate it, but that was in the beginning.

Now I feel like a lot of the choices of the providers that I work with when they're choosing a treatment for a patient is they're thinking about that overall survival that we are seeing and then they'll decide a treatment based on that. I see them more likely to start with ribociclib, more likely to lean toward abemaciclib, but really when it comes down to it, it really depends on what drug interactions there could be. Some of these medications interact with some antidepressants that we have patients on, so it might be just choosing that, or their insurance company wants them to try palbociclib before they try ribociclib. We use them all sort of randomly, I think, in my opinion for our patients.

Mikel Ross:

Dr. Toppmeyer?

Dr. Deborah Toppmeyer:

Yeah. I think an important presentation was Angie DeMichele's at San Antonio looking at real world evidence for palbociclib, and using a Flatiron database of about 1,400 patients and really adjusting for differences within the patient population. Actually, there was both a progression-free survival and an overall survival advantage, and I think that that makes people more comfortable. She published it in breast cancer research and I think that's an important presentation because I think that again, one needs to understand, how do we have identical progression-free survival, but yet such differences in overall survival? I could make more of an argument for abema[ciclib], since it's different. It's not a selective CDK4/6 inhibitor, but I have a little bit of difficulty rationalizing why that would be the case. I think we just have to be very careful about that, but I think her presentation and the paper is critically important because it says you can use them all.

I do think it's important to think about quality of life issues for a patient. These are patients with metastatic disease. If they're having significant GI side effects, if they're coming in more frequently for EKGs than they need to. These are all factors that I take into consideration. The neutropenia associated with palbo[ciclib] and ribo[ciclib] are different than those associated with chemotherapy-induced neutropenia. I tend to really prescribe more palbociclib in the metastatic setting. I do feel very comfortable based on the Flatiron data, and I think that I do struggle with understanding how there could be such a significant difference in overall survival when the progression-free survival is really identical. I think you have to take all of those things into consideration, particularly the quality of life issues that you are dealing with a patient population with metastatic disease.

Mikel Ross:

Again, I so appreciate your comments and your insight and you've laid it out well. You only have 3 choices, and my takeaway from it is no matter what you choose, you're not wrong. What I'll often tell patients when they say, well, which one's better? I'm like, it depends. I can't tell you if you're hungry that chicken, steak or fish is better. It just kind of depends on what you're in the mood for and you can get full with any of them. Now, that's kind of an old country boy's way of looking at it, but I think it kind of fits where we are here. For example, with ribociclib, we do have to think about drug-drug interactions, QTC prolongation. We think we don't see it that often, but you'll get that alert from OptumRx that says, oopsy-daisy, and you'll go, okay, forgot about that one. Then there are even patient characteristics that will make a QTC prolongation a bit more likely, of which electrolyte balances are one of those. Guess what we have in metastatic breast cancer? Electrolyte abnormalities.

Once again, I think the great takeaway is they're all amazing. They've all added so much. They're so much better than a retreaded AI, and you're not wrong. I don't know. If I'm missing something, I'd love to hear your thoughts.

Dr. Deborah Toppmeyer:

No, and I also wonder about the dosing of ribociclib. If we really needed to go to 600. I think many of these agents, they don't have to be given at their MDT, and I think that also incurs toxicity and patients coming off trials, et cetera, and compliance. I think that's important to consider as well, but I completely agree with you.

Mikel Ross:

Yeah. Just switching a little bit, the one area where I think we are still a data-free zone is how do we sequence these agents? We've kind of been trying to figure that out in the metastatic setting before too long with patients that have seen abema in the early-stage setting. We're also going to have to think about if they recur after the 2 years of abema, how long disease-free survival interval do we really feel comfortable with to say that they're not failing a CDK4/6? Where do you guys... kind of data-free, but what do you see in practice and what are your thoughts on sequencing these drugs? Sarah?

Sarah Donahue:

I actually have not had a patient yet recur after being on adjuvant abemaciclib. I think that that's great news. It could be that there are patients that I've treated before, I just haven't seen them in a while, but my feeling about this, if I saw a patient right now that had a recurrence within a year of being on a CDK4/6 inhibitor adjuvantly would be not to use that again. I would be worried. I'd be really worried about putting them on even a different one if it was within a year. I don't know that there's any data out there on this and I don't know what's being done in practice, honestly.

Mikel Ross:

Yeah. I always say, as a nurse practitioner, I play within the lines and I color within the lines, but Dr. Toppmeyer, as I always, say physician strategy, advanced practice providers, we're great at execution. Would you feel comfortable coloring outside the lines here?

Dr. Deborah Toppmeyer:

I think we have no data. If a patient was on adjuvant abemaciclib, if they recur, it doesn't make sense to try another hormonal therapy with another CDK4/6 inhibitor. As you recall, the MAINTAIN trial asked exactly that question. When patients progressed on a hormonal therapy with a CDK4/6 inhibitor, in more than 80% of the cases it was palbociclib, they were switched to ribociclib. What that study showed was there was an impact and there was an improvement in progression-free survival. Not a huge amount, but we also don't know was that from a crossover for a different hormonal therapy, although the PACE trial that was presented by Erica Mayer at San Antonio did not suggest this was fulvestrant, and then fulvestrant with palbo, and then an immunotherapy that only the immunotherapy arm actually benefited. Maintaining the hormonal therapy CDK4/6 inhibitor while changing the hormonal therapy did not seem to make a difference. I think you have somewhat conflicting data, but again, it wasn't that the palbociclib was switched to a different CDK4/6 inhibitor, but if we're talking about adjuvant setting to metastatic setting, there are no data.

Mikel Ross:

Okay, great. One last question and then I'd like to move on to our case study. When we look at the management of stage 4 disease, we often try to bucket it a little differently between, I'll look at metastatic, not very heavy burden of disease patient, versus patients that may be rapidly progressing or perhaps in visceral crisis. Where do you think we can rest in terms of using a hormone therapy versus traditional chemo in those patients? Is that a false difference? Is that a distinction without a difference, and do we manage them the same or differently? Dr. Toppmeyer, I'll let you go first.

Dr. Deborah Toppmeyer:

I think there was also a very nice presentation at San Antonio, the RIGHT Choice trial. In that trial, in patients who had visceral disease and impending visceral crisis or patients with non-visceral disease but very symptomatic disease were randomized between physician choice of chemotherapy versus ribociclib and hormonal therapy. What they saw was, and not surprisingly because you're talking about a much more targeted treatment, but what you actually saw was a doubling of progression-free survival on the patients who received a CDK4/6 inhibitor with hormonal therapy. Again, our knee-jerk response is to say, this is very aggressive treatment. Patients need to respond, but better targeted therapy is really the answer and the right choice, I think really has now provided the data to support physicians or providers taking that route to treat their patients with targeted therapy as opposed to this very shotgun chemotherapy approach. I think that was a very, very important trial and very reassuring to say somebody's got extensive liver metastases, lung metastases that does not preclude the use of hormonal manipulation with a CDK4/6 inhibitor and the default should not be chemotherapy.

Mikel Ross:

Once again, a patient of mine that we saw in clinic. A 66-year-old female with a left breast cancer in 2015, hormone-sensitive, HER-2 negative, Oncotype of 22. Postmenopausal, so we now know we would not be offering chemotherapy even though at that time that might have been a little bit more of a judgment call. Had a lumpectomy, radiation. Did forego chemotherapy. Also decided to not take hormone therapy. Then 7 years later she presented with a 2.3-centimeter fungating sternal skin lesion, which the patient had had for 6 months or so. We did a PET scan, looked like we had a disease in the bones, the lymph nodes, the pleura, and then of course the sternal side. Biopsied that chest wall, and the report came back as metastatic breast cancer morphologically similar to the initial breast cancer, ER 70%, PR 20, and HER-2 negative completely. Not even low, as we have a new category. HER-2 negative at zero.

We provided this patient a recommendation of a first line AI and CDK4/6, but she stated, and you can kind of tell in her history, someone that's maybe got some different approaches or thoughts about care, “I've always been a less is more kind of person and I'd really rather not have those extra toxins in my body.” What are some of the key points with that patient? Ultimately, as I say, you know what? You ultimately get to drive this bus. I just can offer you the best data-driven recommendations. Dr. Toppmeyer?

Dr. Deborah Toppmeyer:

Yeah. I say this all the time to my patients, quoting my Peloton instructor Dennis Morton, “I make suggestions. You make decisions.” It's always about that, and it has to be a dialogue. There's no faster way to shut the door between you and the patient when you are somewhat dogmatic and aren't listening to what they have to say. Clearly this woman has made decisions that most patients would not have. They would've typically taken hormonal therapy. I agree with you. We don't have sequencing data, but the most I would like to at least get her, or I should say at the very least, get her on hormonal therapy.

Once again, she is a type of patient that if she has toxicity, then she's going to be much more reluctant to follow through and be compliant, and say bye-bye. I think starting her off with an AI, for example, and then if and when, I should say, she has progression, then using fulvestrant with a CDK4/6 inhibitor would be reasonable. I wouldn't say to her, no toxins in your body didn't serve you well the first time, but I think you have to meet the patient halfway and I think a good halfway mark in a patient like this would be, “Okay, I hear you, but these are the data. Talk about the data, but the decision is yours. Can we compromise and at least start some hormonal therapy?”

Mikel Ross:

Sarah, have you met this type of patient, had this kind of situation, and Dr. Toppmeyer spoke to, we really don't have sequencing data, so we really can't stand firmly and say you absolutely must have a CDK the very first line in order to optimize your overall survival.

Sarah Donahue:

Yeah. No, I've definitely seen this patient. I've met this exact one, I'm sure. I will ask them what their goals of therapy are? What is it that they want from us? What is it that they need? Are they having pain from their sternal lesion? Is she having shortness of breath from fluid in the pleura? Is there something that's bothering her that she wants to go away, and how can I help her achieve that? If it's by convincing her to take an aromatase inhibitor, then that's what I'll do, but just figuring out what it is that she wants because I know what I want. I want to put her on treatment and stabilize her disease and shrink some stuff. I have goals, but they may not be her goals.

Then if I say, okay, let's start an aromatase inhibitor, let's start something on you and a patient says to me, “I'm worried about toxins in my body,” I'll ask them what they are worried about exactly. I have patients that come and say, “I'm worried about the side effects of this drug that you told me about last time. I went and read about it and I'm really worried and I don't want to start it.” I say, “Okay, well what were those side effects?” We'll go through each one of them and I'll talk about them and talk about whether or not it's a known side effect that's common with a medication or if it is a known side effect, how we could manage it, how I could help them with it, but really just taking the time to listen to what it is that they want so that I can help them because I'm serving them. That's my job is to serve my patients.

Mikel Ross:

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 online 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 give the very best for our patients.