Listen to Drs William J. Gradishar, Heather McArthur, and Joanne Mortimer address key questions on the use of CDK4/6 inhibitors in HR-positive/HER2-negative breast cancer treatment. The discussion covers genomic testing options, adjuvant treatment duration, toxicity management topics, and how the available clinical data and updated guidelines influence therapeutic decisions.
In this episode, Drs William J. Gradishar, Heather McArthur, and Joanne Mortimer address audience questions from a recent live event on the use of CDK4/6 inhibitors in patients with early and metastatic breast cancer, including:
Presenters:
William J. Gradishar, MD, FACP, FASCO
Betsy Bramsen Professor of Breast Oncology
Robert H. Lurie Comprehensive Cancer Center
Northwestern University
Chicago, Illinois
Heather McArthur, MD, MPH, FASCO
Professor, Department of Internal Medicine
Clinical Director, Breast Cancer Program
Komen Distinguished Chair in Clinical Breast Cancer Research
UT Southwestern Medical Center
Dallas, Texas
Joanne Mortimer, MD, FACP, FASCO
Vice Chair, Medical Oncology
Professor, Division of Medical Oncology & Experimental Therapeutics
Associate Director for Education and Training
Baum Family Professor of Women’s Cancers
City of Hope Comprehensive Cancer Center
Duarte, California
Link to full program:
https://bit.ly/4osHLTm
This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Dr. William Gradishar (Northwestern University): The first question that came in was, why is Oncotype DX preferred over MammaPrint? Is there a place or a setting where you might use both tests in clinic on a given patient? Joanne?
Dr. Joanne Mortimer (City of Hope): I think we have the longest experience with Oncotype, that is for sure, is being prognostic and predictive. Certainly, MammaPrint has many of the similar characters. I think have used both in the clinic. I tend to use Oncotype more often because we have more data on that, especially recently with discussions about whether anthracyclines are beneficial in patients with extremely high Oncotype scores.
MammaPrint does have a role, and we certainly use it in screening patients for certain clinical trials.
Dr. Gradishar: I would echo the same sentiments. I mean, we have been using Oncotype seemingly forever at this point. We have huge data sets that support its use. MammaPrint has certainly been an element that is used to determine certain clinical trial eligibility. There is even some data as well with MammaPrint scores determining who might be eligible for an anthracycline. But like you, our typical go to for most patients is the Oncotype test.
One thing I think we probably both share the same sentiment is we try not to do both tests in the same patient.
Dr. Gradishar: Heather, what are your thoughts on this?
Dr. Heather McArthur (UT Southwestern): Oncotype is the preferred genomic assay in patients with node-negative disease. But NCCN guidelines support either Oncotype or MammaPrint for node-positive disease for postmenopausal women.
Premenopausal women automatically get a recommendation for chemotherapy if they have node-positive disease. But genomic assays are very helpful for postmenopausal women with node-positive disease.
You can use either in that space. I typically use Oncotype, but that reflects my background because I trained at Sloan-Kettering and that was a key site for Oncotype development.
Dr. Mortimer: In the adjuvant setting, would the difference in treatment duration influence the treatment choice between abemaciclib and ribociclib. Bill?
Dr. Gradishar: Well, it may depending on the patient. From my standpoint where you have to get into this discussion about side effects and even though you start out with the idea of giving ribociclib for three years, some patients may or may not make it to three years with respect to tolerating the treatment.
The goal is to stick with the treatment design according to the protocol abemaciclib for two years, ribociclib for three. Some patients hearing the duration of that second drug may or may not find that attractive or something that they are willing to do.
In that circumstance, I think the alternative shorter duration abemaciclib might be a better choice. But at the same time, you have to take into account that there might be a difference in side effects between the two drugs. Duration versus side effects may be an issue you have to think about with each of these drugs individually.
Dr. Mortimer: Yeah, the educated consumer has probably been on sites to know what the side effects abemaciclib cycle of are and ribociclib. I guess in my experience most patients have strong feelings about one or the other as this has gone on. You are trading off diarrhea and short term versus longer term and maybe fatigue, maybe with 400 milligrams a day of ribociclib on a 21, 28-day cycle.
Dr. Gradishar: Yeah. I think we have gotten probably a little bit better at dose reductions in managing abemaciclib, but some patients clearly do not like diarrhea.
Dr. Gradishar: Heather, what has been your experience?
Dr. Heather McArthur (UT Southwestern): So monarchE, which looked at adjuvant abemaciclib in high-risk patients administered the CDK4/6 inhibitor for two years. Whereas the NATALEE study in the adjuvant setting administered ribociclib for three years. So there is that difference between two years and three years.
I think it really depends on the patient population and individual specific considerations. If a patient had a lot of diarrhea or GI toxicity with their chemotherapy, and again, the majority of patients who were treated on monarchE and NATALEE had chemotherapy. So this is a high-risk population.
If patients had GI toxicity with chemotherapy, I would probably favor ribociclib. If patients had cardiac history or who were on drugs that had QTc prolongation, which is one of the issues with ribociclib. In that case, I would typically favor abemaciclib. They really are tailored treatment recommendations based on patient and tumor-specific characterizations, but not necessarily around duration, since patients will be on hormone therapy for five years or longer and are willing to accept two versus three years of concomitant therapy for the most part.
Dr. Mortimer: What is your feeling on discontinuing abemaciclib for a patient while on vacation or during a family event due to adverse events caused by the medication?
I am presuming that this question emanated from patients who have a lot of GI toxicity with abemaciclib, and frequently patients do not go out to eat. They avoid being at parties. They avoid eating at parties, I should say, because of fear of GI toxicity.
I tend to be fairly lax and do let people discontinue their abemaciclib during vacations or family events. I do not know that there is any data that said that says that is good or bad, but the duration of abemaciclib, certainly in the adjuvant setting of two years, I just add on that time period that they were off towards their end date.
Dr. Gradishar: Again, I think we are on the same page. It would not be just restricted to abemaciclib if somebody was having a vacation or a major family event regardless of the therapy they are on, I would probably try to mitigate any side effects and hopefully allow them to enjoy whatever the event was, if that meant delaying their therapy. If they are going off somewhere on vacation for four months, maybe not so much. But for a shorter period of time, I have no issue whatsoever with doing that similar to you.
Dr. Gradishar: Heather, what are your thoughts on this?
Dr. Heather McArthur (UT Southwestern): I do not typically do that. The primary symptom with abemaciclib. About 90% of patients on adjuvant abemaciclib get diarrhea within the first two months and it abates after that. It requires excellent education and intervention with a low threshold for intervening for diarrhea.
The first signal of loose bowel movements we suggest that patients start Imodium. Again, it is really primarily about getting them through those first two months on therapy. Then after that, patients tend to tolerate treatment extremely well from a GI perspective. Holding or discontinuing during vacation or other family events is not typically indicated.
There was interesting data looking at abemaciclib dose escalation as a strategy for mitigating GI toxicity. I have a patient facing clinical pharmacist. We have a lot of education upfront. I have not had a lot of issues with abemaciclib specifically. But I know that it is a challenge that plagues the community. It is very encouraging to see that dose escalation at the onset to build up to therapeutic doses is safe and effective and well tolerated.
I would also point out that we have a lot of data now from older populations showing that they derive the same benefit, although there seems to be a lower threshold for discontinuation of medication. It is encouraged that if toxicity occurs in older populations, that patients are recommended to receive a dose reduction rather than discontinuation because older patients do derive the same benefits.
Dr. Mortimer: Any thoughts on why palbociclib did not show a benefit in the adjutant setting?
Dr. Gradishar: For many people, they were very persuaded by the data with abemaciclib and ribociclib showing a survival benefit. Part of it may be a function of how the trial composition in terms of patient characteristics could account for it. Of course, there were subsequent real-world experiences that have been published several times now, suggesting that palbociclib also confers a survival benefit. But in the registration trials, it did not show that.
Again, I do not have a good answer. I mean, we try to be evidence driven, and at least in the registration trials, we do not see that benefit. But if the other two drugs disappeared, would I use palbociclib in the setting? Sure.
Dr. Mortimer: Yeah. I think the most impressive data is in, like, patients with visceral crisis disease, where it does seem that ribociclib and abemaciclib may confer some advantage over palbociclib. But in older women and patients with bone-only disease, it is hard to argue that one is more superior
Dr. McArthur: Yes, I think, for example, in the PALLAS study, there were a lot of rules around absolute neutrophil count that incurred treatment holds or discontinuation. Whereas in the, for example, monarchE study looking at adjuvant abemaciclib, the holds and discontinuation were around things like diarrhea that could be clinically managed. But of course you cannot clinically manage low absolute neutrophil count in the adjuvant setting.
I think that the very strict parameters around hold and discontinuation for palbociclib in the curative intent setting that we are really focused or incurred by uncontrollable issues like neutrophil count, undermine the potential effectiveness of that strategy in that setting.
Dr. Gradishar: Can you comment on how you are managing renal issues, meaning specifically an increase in creatinine that might be observed with abemaciclib, but it has also been seen with other CD4 six inhibitors, including ribociclib? In that setting, are you continuing therapy if the creatinine is high but stable? Then as a follow up, are you using cystatin C to guide your therapy in that setting?
Dr. Mortimer: Yeah. The important thing to know about renal changes with abemaciclib is that they are not related to the drug, but how we measure serum creatinine. It blocks the ability to assess creatinine. In the course of that you get higher levels in the blood. High elevation of serum creatinine with abemaciclib is common. It persists for probably 96 hours afterwards. It is not an indicator of renal toxicity though.
If you really want to know what the patient’s serum creatinine you need to do a cystatin C. I personally have never seen anybody in ribociclib have an elevation in their serum creatinine. I know there are reports, but they are pretty rare. It really is abemaciclib for which the renal issues show up. Again, it is a false elevation in the serum creatinine not real renal toxicity.
Dr. Gradishar: I think the only thing I would add because I completely agree, it is the pseudo kidney insufficiency. Although it is described with ribociclib, I have not seen it either. I guess the only thing would be is if you have any other comedications that are on board that could be causing any impairment of the kidneys, you have to take that into account as well. But absent that, if they just have a mild elevation and it is not going anywhere, I would probably continue the therapy. Whether I do cystatin C or not, I guess would depend on what the trajectory is just to clarify that. Again, I think we agree completely.
Dr. Gradishar: Heather, what has been your experience?
Dr. McArthur: I have had fortunately only one patient with whom I have worked with nephrology and done a cystatin C and this was in a patient who had only one kidney because they had undergone nephrectomy, and so we were being very cautious. But she was able to continue on treatment once we had done that cystatin C to confirm that it was a false elevation in creatinine.
Dr. Gradishar: On the same issue of whether or not these medications cause any other side effects, it has been described really with all of the CD4/6 inhibitors, that there is an elevation in the risk of developing a DVT, which lends itself to the question of whether there is any role for prophylaxis with low-dose aspirin. I do not know if you have ever been in that situation where you have considered that, Joanne.
Dr. Mortimer: I have not. There certainly is a literature amongst the hematologists looking at whether the incidence of DVT is high enough with the CDK4/6 inhibitors that prophylaxis is appropriate. I have not done it and there really is no data to support it, although there certainly is a little talk about considering it.
Dr. Mortimer: Heather, do you have anything to add?
Dr. McArthur: I am not aware of any data for low-dose aspirin, although notably I do not give ribociclib together with tamoxifen for patients who have high-risk disease. I would typically choose abemaciclib together with tamoxifen under that situation.
Dr. Mortimer: How do you manage radiographic ground glass opacities without respiratory symptoms. I think this is obviously pertinent for the CDK4/6 inhibitors. It is probably more pertinent for patients who are getting T-DXd, because our radiologists seem to be reporting this out so much more, and it is causing a lot of angst.
Dr. Gradishar: I also do not have a very evidence-based answer for this. I think one of the observations that has been made is that when the concern about interstitial lung disease became very clear with T-DXd, every drug we use, they start going back and looking at x rays. Now we see whether it is everolimus, whether it is a CDK4/6 inhibitor. There is always some tiny fraction of patients that seem to get these ground glass opacities.
Again in the absence of any respiratory symptoms for most patients, certainly with the CDK4/6 inhibitor, I would not discontinue therapy. I would probably now be obligated to look at the scan again more carefully and in subsequent scans. In the absence of any hypoxia or other respiratory symptoms, I probably would not do anything different. How about you, Joanne?
Dr. Mortimer: Yeah. The latency in some of the reports for development of pneumonitis is shorter for abemaciclib than it is for ribociclib. It is like 50 days versus 200 plus days. But in the absence of symptoms, I do not usually change anybody. It makes me worry a little bit, but I do not change anything.
Dr. Mortimer: A patient who had hepatotoxicity, who had liver enzyme elevations on ribociclib. The question is, can they go on to another CDK4/6 inhibitor? Or does the fact that they had a significant toxicity from ribociclib mean that they are not going to be able to tolerate any of the other two agents? I think this has also come up with pneumonitis as well with interstitial lung disease. If you have a toxicity from one, are they mutually exclusively going to have the same problem.
Dr. Gradishar: I personally do not know the answer to that. But I think if, for example, if somebody’s LFTs did rise but came back to normal on discontinuation, I might consider an alternative. I am not aware of any data. Maybe you can educate me on that, Joanne.
Dr. Mortimer: Yeah. The data that for trying another CDK4/6 inhibitors was largely case reports. There are case reports for both of those for using in other agents with hepatotoxicity with ribociclib. Ribociclib really does seem to be the one that causes hepatotoxicity. I personally have a patient whose bilirubin went up to 14, and she is now on abemaciclib and doing fine. But at the same is true also of interstitial lung disease, where if you switch to a different CDK4/6 inhibitor that you may not get the same toxicity.
Again, most of this is case reports. I think the hepatotoxicity is better well-defined because it seems to be the problem with ribociclib more so than any of the other two.
Dr. Gradishar: If a patient is tolerating abemaciclib and a nonsteroidal aromatase inhibitor, can they stay on this regimen if the disease does not progress indefinitely?
Dr. Mortimer: I think when you are on something that works, you do not stop it generally unless there is a really good reason. But I think most of us keep this patient on the abemaciclib with the non-steroidal agent as well.
Dr. Gradishar: Yeah. We really have not gotten to the CLEOPATRA anti-HER2 approach here where you stop the chemo and keep the HER2 therapy going. I too would keep the combination going as long as the patient was tolerating it.
Dr. Gradishar: Heather, what are your thoughts on this?
Dr. McArthur: Yes, we would continue those therapies indefinitely. On average, CDK4/6 inhibitor with aromatase inhibitor controls disease in the first-line setting for on average two years. But certainly there are exceptional responders. We continue that therapy for as long as it is working.
Dr. Gradishar: Would you use ribociclib with inavolisib instead of palbociclib? Because as you recall in the INAVO120 study palbociclib was combined with inavolisib and endocrine therapy. But because there is data that would suggest perhaps ribociclib is a better CDK4/6 inhibitor in the metastatic setting, would you switch out palbociclib and put in ribociclib instead?
Dr. Mortimer: I would have to say, it is hard to justify going from palbociclib to ribociclib because the evidence-based data is with palbociclib. Although we certainly have spent a lot of time in the last several years trying to decide if one of these drugs is better than the other, it seems as though we are using them in different settings right now, so I actually have not substituted ribociclib. I have used palbociclib only because of the data that was published.
Dr. Gradishar: I agree. I mean, again, the triplet has been used by me sparingly. I have not done it that many times. Only in the patients who are rapid progressors. But I have stuck with the treatment protocol and not switched out the CDK4/6 inhibitor either.
Dr. Gradishar: Heather, what has been your experience?
Dr. McArthur: I am sort of a stickler for how clinical trials are conducted. I would administer only the combination of drugs that was administered on that study.