CDK4/6 Inhibition in Breast Cancer: Expert Perspectives on Integrating Guideline Updates and Recent Advances Into Practice

 

How do we define high-risk hormone receptor-positive/HER2-negative breast cancer? So conventionally we use staging parameters including tumor size, nodal status and high grade, which have been established to affect recurrence risk and improved prognostic accuracy and gene expression signatures.

 

High proliferation Ki-67, which is something that we debate all the time in our tumor boards, because we see a lot of discordance in terms of grade and Ki-67 and interested to hear how you're discussing that in your tumor boards, but very subjective interpretations and maybe associated with lower ER levels that could increase the risk of recurrence.

 

And failure of preoperative endocrine therapy to suppress Ki-67 predicts poor outcomes in women who receive preoperative endocrine therapy. The luminal B, HER2 enriched and basal like or high-risk hormone receptor-positive/HER2-negative breast cancers. And we can talk about how we use the various genomic assays because there are several. And I often have patients who come in to see me who have already had those genomic assays pre-ordered by their surgeons, which definitively impact how I think about talking to patients about their risk and risk of recurrence.

 

And endocrine therapy resistance is a key feature of high-risk hormone receptor-positive, HER2-negative, ER-positive breast cancer that recurs within 2 to 5 years.

 

[00:45:13]

 

Risk of Distant Recurrence After 5 Yr of Endocrine Therapy

 

And so here you see the risk of recurrence. This is data, a meta-analysis of patients with ER-positive breast cancer that was diagnosed between 1976 and 2011. So you could argue that this does not reflect a modern treatment era. But all of these patients receive 5 years of endocrine therapy.

 

And you can see that conventional staging in the setting of endocrine therapy has impact in terms of prognostic impact here. Certainly, in an updated analysis, 20-year risk of distant recurrence was a third lower for node-negative, ER-positive breast cancer that was diagnosed before 2000.

 

But certainly we've had a number of innovations since that point, including CDK4/6 inhibitors that have changed this forecast for our patients, thank goodness.

 

[00:46:06]

 

2022 ASCO Guidelines: Biomarkers for Adjuvant ET and CT for HR+/HER2- EBC

 

Here are the 2022 ASCO guidelines based on biomarkers for adjuvant endocrine therapy and chemotherapy for hormone receptor-positive/HER2-negative breast cancer.

 

In the premenopausal category, we really should only be doing genomic testing in those node-negative patients, and oncotype is the preferred genomic assay. In the node-positive, there is insufficient evidence to recommend a biomarker in that setting. However, we have seen some data not in node-negative disease, but in node-positive disease from RxPONDER looking at AMH testing in that setting and trying to refine our understanding about perimenopausal patients. So there's maybe some nuance there.

 

In postmenopausal women, node-negative and node-positive patients should have genomic testing.

 

[00:47:02]

 

Risk Assessment Algorithm to Inform Systemic Adjuvant Therapy Selection in EBC

 

So here's the risk assessment algorithm to inform systemic adjuvant therapy selection in early stage breast cancer. For patients who don't have metastatic disease, who are high risk of recurrence, who are candidates for neoadjuvant chemotherapy or endocrine therapy should be randomized or considered for neoadjuvant endocrine therapy based on absence of mutation status.

 

[00:47:29]

 

Adjuvant EBC Trials With CDK4/6 Inhibitors

 

So we've seen a number of studies looking at adjuvant CDK4 inhibitor therapy in addition to adjuvant endocrine therapy in our high-risk populations. And this is a summation of those studies. So we've seen PENELOPE-B and PALLAS, which looked at palbociclib. Those studies were negative studies, that did not support the use of that specific drug in the adjuvant setting. And we can talk about the reasons why there might be limitations around the interpretation of that data.

 

But the monarchE and NATALEE studies are the studies that led to the FDA approval of abemaciclib and ribociclib, respectively, in the adjuvant setting.

 

[00:48:16]

 

monarchE and NATALEE Trial Populations

 

And it's been a little tricky to understand who you might consider for abemaciclib vs ribociclib. So this is actually a chart that we've actually posted in our clinic area so that people can think about who the right patients are for specific CDK4/6 inhibitors, because there are pretty nuanced differences between the 2 studies.

 

[00:48:35]

 

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

 

But in monarchE, there were 2 cohorts. As a reminder, the first cohort was based on high-risk clinical pathological features, 4 or more lymph nodes, 1 to 3 lymph nodes with at least grade 3 disease or large tumor size greater than 5 cm or more. And cohort 2, which was based on high Ki-67, which was, of course, the initial approval of abemaciclib was based on a high Ki-67 greater than 20%, and then it was subsequently changed to high-risk disease.

 

But those patients who were deemed high risk were stratified 1-to-1 to receive adjuvant abemaciclib for 2 years vs standard endocrine therapy.

 

[00:49:24]

 

monarchE: Sustained iDFS Benefit in ITT at 5Y

 

And the follow up period was - or sorry, the primary endpoint was invasive disease-free survival. And you can see here, although the initial data report was encouraging, we've seen more recent data. At 5 years, there's a 7.6% improvement in invasive disease-free survival. So clearly a benefit. But again, in a very high-risk population and more than 90% of patients who participate in these trials received chemotherapy. So this is already deemed a high-risk population by virtue of the fact that they already received chemotherapy.

 

[00:50:02]

 

monarchE: Consistent IDFS Benefit Observed in Selected Subgroups

 

But when you look at the subset analyses, you can see very consistent benefits across subgroups, regardless of menopausal status grade status.

 

[00:50:14]

 

monarchE: 5-Yr DRFS in ITT Population

 

And when we look at distant relapse-free survival in the intention-to-treat population, very similar benefits as well.

 

[00:50:24]

 

monarchE: Older Patients Derived Similar Abemaciclib Benefit to ITT Population

 

One of the issues that we faced is dose reductions or early discontinuations in older populations. And we've seen from multiple studies, including the curative intent CDK4/6 inhibitor studies that older populations derive the same benefit from CDK4/6 as the younger populations, so one should pursue dose escalation, which leads to same benefits but not discontinuation in that population. So very important to consider dose escalation before pursuing discontinuation.

 

[00:51:01]

 

monarchE: OS Update

 

You can see here survival update, although way too early to understand whether those 5-year invasive disease-free survival benefits will translate into an overall survival advantage.

 

[00:51:16]

 

Approvals and Recommendations: Adjuvant Abemaciclib + ET

 

So here are the approvals and recommendations. You can see FDA and ASCO and NCCN. They're slightly different. And maybe Dr Gradishar will speak to the NCCN. But different nuance. And again the abemaciclib approval was originally supported by a Ki-67 greater than 20%, which was dropped, hard to believe 2 years ago now, for high-risk disease.

 

[00:51:47]

 

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

 

So NATALEE was the second study that was reported out. So this was looking at ribociclib with endocrine therapy in intermediate to high-risk hormone receptor-positive/HER2-negative disease. Included pre and postmenopausal women. And this study really stood out because it included node-negative disease, which the monarchE study did not include.

 

And women were randomized to receive hormone therapy with or without ribociclib. Here the CDK4/6 inhibitor is administered for 3 years, whereas monarchE, it was 2 years.

 

[00:52:24]

 

NATALEE: iDFS in ITT Population

 

And same invasive disease-free survival, primary endpoint but a very different population, again, including the high-risk known negative population which was not included in monarchE.

 

So here's the invasive disease-free survival in the intention-to-treat population. You can see in almost 5% improvement at the 4-year landmark analysis, with median follow-up of 44 months and a benefit that was observed regardless of nodal status.

 

[00:52:58]

 

NATALEE: IDFS by Nodal Status

 

And here is just subset analysis as well.

 

[00:53:02]

 

NATALEE: IDFS by Age

 

What's the benefit by age. You see very similar benefits for those patients who are less than 65 vs those who are older than 65. The older I get, the more offensive I find these cutoffs. So just saying.

 

[00:53:20]

 

NATALEE: DDFS and OS at 4-Yr Landmark Analysis

 

And very consistent benefit for distant disease-free survival. Again, it's too early to see those invasive disease-free survival and distant disease-free survival advantages translate into overall survival.

 

[00:53:36]

 

Different Eligibility, Different Populations

 

And this again is a chart that we put up in our own clinical area to differentiate patients who potentially are candidates for ribociclib vs abemaciclib in the curative intent setting. And it is very nuanced. And I think we all have our own like ingrained feelings about who should get access to what, and what drugs were most comfortable using. But to be true to the study designs and the approvals, this, I think, brings us back home to where we should be thinking about our patients and who qualifies for what opportunity.

 

[00:54:17]

 

Approvals and Recommendations: Adjuvant Ribociclib + ET

 

We've seen this previously.

 

[00:54:22]Oncotype DX Not Predictive of Adjuvant Abemaciclib Benefit in monarchE

 

So oncotype, and we have this conversation in our tumor board all the time. Can we give CDK4/6 inhibitors instead of giving - giving chemotherapy. So more than 90% of patients who received a CDK4/6 inhibitor on trial received chemotherapy. We have no data that really informs whether there is a select population of patients who could get CDK4/6 inhibitor with optimized endocrine therapy instead of chemotherapy, and those are the trials that we are really needing. And Oncotype is predictive of benefit but doesn't absolutely tell us benefit in that setting.

 

[00:55:03]

 

Optimizing Therapy: Adjuvant Chemotherapy vs CDK4/6 Inhibitors

 

There are trials, ADAPTcycle and RxFINE-LOW that are looking at adjuvant CDK4/6 inhibitor therapy vs chemotherapy. And we need that data. But that data is forthcoming. And again that's something that we struggle with in our tumor board. Interested to hear about your tumor boards. But we struggle with that all the time. Can we optimize endocrine therapy and add in CDK and not offer chemotherapy?

 

[00:55:32]

 

Let's Revisit Our Case

 

Patient Case 1: Woman With Grade 3 ILC and 2 Positive Nodes

 

So if we go back and look at our patient case, women with grade 3 invasive lobular carcinoma, 2 positive nodes. She's 58, postmenopausal, 3.5-cm breast mass, ER 80%, PR 30%, HER2-negative biopsy. The FNA of the palpable right axillary lymph node is positive. BRCA testing is negative. She undergoes right lumpectomy with sentinel node biopsy, 4 cm, 2 out of 3 lymph nodes positive lobular. So that happens, right, more extensive than you expect. Has an oncotype test 26, gets TC. Radiation comes back to clinic.

 

[00:56:25]

 

Posttest 1

 

In addition to extended duration adjuvant endocrine therapy, what additional systemic therapy would be most appropriate for this patient? So again, T2, lymph nodes involved. She had chemotherapy. What endocrine therapy would you provide?

 

1. So none; endocrine therapy alone; Sorry, I didn't read the answers;
2. Abemaciclib only;
3. Ribociclib only. And these are obviously above endocrine therapy;
4. Abemaciclib and ribociclib; or
5. Any of the 3 CDK4/6 inhibitors.

 

Yeah. So kind of a trick question because she had nodes involved. So she would have qualified for monarchE or NATALEE, based on high-risk. So pre was 48%, post 73%. So terrific.

 

[00:57:42]

 

Posttest 1: Rationale

 

So this patient is at high-risk of recurrence. She had one to 3 positive lymph nodes. Grade 3 disease, high oncotype score. Palbociclib hasn't demonstrated benefit and isn't FDA approved in this setting. So abemaciclib and ribociclib would be appropriate options here.

 

[00:58:00]

 

Key Takeaways for Early HR+/HER2- Breast Cancer

 

So key takeaways for early HR-positive/HER2-negative breast cancer. So abemaciclib and ribociclib are both health authority approved in the adjuvant setting for high-risk early stage breast cancer. However, you define high-risk, selection of adjuvant CDK4/6 may vary based on patient disease characteristics, comorbid conditions, concurrent medications, and potential adverse events.

 

Ribociclib is the only drug that's approved for node-negative early-stage breast cancer that's high-risk. The most common adverse events include neutropenia and liver-related adverse events with ribociclib and diarrhea with abemaciclib. So about 90% of patients get diarrhea with abemaciclib. And then after the first 2 months, it dissipates and they improve. So you just have to aggressively manage that upfront.

 

Adverse event monitoring and dose modifications are, of course, opportunities and available when important.

 

Thank you.

 

[00:59:10]

 

Aligning Current MBC Treatment With Current NCCN Guidelines and Expert Recommendations

 

Dr Gradishar: Since we have just - we're just a tad above the schedules. So there was a question that came through and it was with reference to choosing Oncotype vs MammaPrint. And number 1, if you have a preference, if there's a role for either - or for both of those, could you think of distinct ways that you might be able to?

 

Dr McArthur: So Oncotype is the NCCN endorsed approach for node-negative disease. And I think that's the most robust data in that setting. Oncotype and MammaPrint are both approved in node-positive, 1 to 3 node-positive, so N1 disease. So you could choose either. I personally use Oncotype more consistently. I like how it's reported. I like the ER/PR, HER2 information that it provides.

 

But we had a tumor board case yesterday where we had a lobular cancer that had low oncotype. And our lobular expert was advocating for MammaPrint in addition to Oncotype. So as an adjunct because she was suspicious based on a high Ki-67 that there might be a more basal phenotype there.

 

Dr Gradishar: Yes. I was going to just say before you said that case, don't order 2 tests and then, you know, there may be very select situations like the one you described.

 

Dr McArthur: Actually talked her out of it.

 

Dr Gradishar: Yeah, yeah. But I - I guess you do get a better sense of the subtype perhaps with MammaPrint. But in terms of predictive, in the node-negative setting and predictive for chemotherapy benefit, the evidence is better with oncotype. They're both prognostic.

 

Dr McArthur: I think what we are anxious to see is not just predictive chemo, yes, no, but exactly what kind of chemotherapy would be prescriptive, right? Because we have a lot of variation. So I still use CMF, and that's heresy in a lot of places. But it's a 50-year-old regimen that's very effective and is equivalent to AC. There's a lot of TC use, and ACT. So it doesn't tell us where to land in terms of that landscape of chemotherapy. And that would be really helpful to further refine.

 

Dr Gradishar: Yeah. Joanne, do you have any comments on that?

 

Dr Joanne Mortimer (City of Hope Comprehensive Cancer Center): [Inaudible].

 

Dr Gluckman: Okay. Yeah. Okay. All right. So we're going to keep on moving along.

 

[01:01:56]

 

Pretest 2

 

All right. So how confident are you in your ability to select CD4/6 inhibitor therapy for patients with metastatic disease based on the guidelines and the currently available evidence?

 

1. Not confident at all;
2. Low confidence;
3. Modest confidence;
4. Confident;
5. Very confident.

 

I feel like I should be sitting on the front porch somewhere with, like, a bottle of something. Okay. All right, so let's run through that - oh, okay. So this - these are the results. So most people feel relatively confident at some level of using the data we have to apply that to patient care.

 

[01:02:49]

 

Evolving Landscape in HR+ mBC

 

So if you look at the sort of timeline, you know, for those of us up on the podium, we spent a lot of our time where there wasn't a whole lot. We were sort of on the left-hand side of the curve for a while - left hand side of the slide.

 

And then, you know, over the last decade or so, we've started to see the emergence of a strategy of partnering endocrine therapy with targeted therapy, as we could really exploit the biology and understood it. And then more recently, you know, there was nothing going on with new endocrine agents. And now we have a flurry of new drugs that you'll be hearing about tomorrow and at the plenary session that may come into the clinic.

 

So, you know, this area is really exploding. And then, of course, a topic we're not talking about tonight is as you get into patients who are refractory to endocrine therapy, what are the other options. And we've seen that antibody drug conjugates have a role in that setting as well. So we'll look at, you know, how the guidelines are sort of set up.

 

[01:03:54]

 

NCCN Guidelines Version 4.2025

 

So just to put up something you can't read, you can't distinguish and you're going to squint, you can't see. I'll just tell you what this says. And it's basically the guidelines. And what is different about them now compared to a decade ago, is they would have been populated largely by monotherapy as a treatment choice for metastatic ER-positive disease.

 

And what's changed over the last decade is obviously this doublet strategy of combining endocrine therapy first with CD4/6 inhibitors and then thereafter, once we started doing NGS testing, identifying patients that may have other mutations and then drug availability, you start to see the inclusion of agents that can either target the mTOR pathway, an older drug like everolimus or PI3 kinase inhibitors like alpelisib, capivasertib, etc.

 

And then more recently, even than that, as we started to understand the importance of ESR mutations, looking at drugs like elacestrant and others that we're going to hear about in the next couple of days, including vepdeg and cami.

 

[01:05:03]

 

Managing HR+/HER2- mBC Patients in 2025

 

So, you know, if we try to distill that information into a single slide, this is one such effort. You know, still raining, sort of as the first step is to give endocrine therapy with a CD4/6 inhibitor. It may become more nuanced, you know, as you heard a few minutes ago. In high-risk patients who are getting a CD4/6 inhibitor as an adjuvant therapy, what do you do if they develop recurrent disease? And it may have some bearing on how long it was since the patient received that CD4/6 inhibitor. And we'll talk a little bit about sequential CD4/6 inhibitors.

 

And then more recently we've come to understand that if you harbor a PI3 kinase in mutation right from the outset, that those are patients that still benefit from CD4/6 inhibitors, but the magnitude of benefit may be less than what you would see in a patient who doesn't have a PI3 kinase mutation. As such, the INAVO120 study generated data that support the idea of giving a triplet with inavolisib, palbociclib and fulvestrant.

 

So if you get past that first-line, then what do you do? Well, we do NGS testing. And after SERENA-6, we may be doing much more of it. Well, here we'll think about that when we hear the discussion from the plenary session. But we're looking for ESR mutations, which may be something that evolves under pressure of therapy. We look for PI3 kinase mutations, which may be present from the get-go, which are in contradistinction to ESR mutations, which, you know, are pretty much something that evolves from very infrequent in the primary tumor to quite common under pressure of treatment.

 

And then, of course, we've come to appreciate other things like PTEN and AKT abnormalities, which may make certain drugs like capivasertib attractive. And we should always remember again that even though we think of BRCA mutations as perhaps more common or frequent in a triple-negative patient population, the universe of ER-positive disease is so much greater than triple-negative disease. The absolute number of patients harboring BRCA mutations are even greater in ER-positive disease. So always think of the possibility that a PARP inhibitor may be something that's useful. And you need - the only way you're going to know that is by doing genetic testing.

 

And then I alluded to the fact that once you're past endocrine therapy, you're refractory, then we start getting into chemotherapy, antibody drug conjugates, T-DXd, sacituzumab govitecan, and most recently Dato-DXd and more to come.

 

[01:07:53]

 

CDK4/6 Inhibitors: ET: PFS in 1L and 2L Treatment

 

So let's talk very briefly about CD4/6 inhibitors. Suffice it to say they're all active. They all work. The registration trials that led to their approval all look the same. They were basically looking at similar populations in the first-line setting, whether it was palbo, abemaciclib or ribociclib. The improvement in PFS was striking. And we've come to realize that probably palbociclib didn't win in that race either. But we'll come to that again in a moment.

 

But I think if you just sort of focus on what the PFS effect is, you see that there's a fairly dramatic improvement in PFS favoring whatever CD4/6 inhibitor you used, the question of superiority of which one is the best really is more of a debate once you get to the endpoint of survival.

 

And then once you're past the first line, and that's a diminishing group of patients who didn't see a CD4/6 inhibitor compared to 5 years ago. But if you were receiving it in the second-line setting rather than the first-line setting, again PFS was improved with the CD4/6 inhibitor. And again, all the drugs look to be beneficial. But the magnitude of the delta was less than what you see when it's used in the first-line setting. So all active drugs you could debate about which one is best, particularly if you're looking at the endpoint of survival.

 

[01:09:22]

 

Median OS of CDK4/6 Inhibitors in 1L HR+/HER2- ABC Trials

 

And again, this is just simply looking at the mean overall survival. And as you go across the trials, MONALEESA, PALOMA, which is the palbociclib data and the MONARCH-3 and MONALEESA-7. Again, there's more of a suggestion of a survival benefit with the trials including abemaciclib and ribociclib than palbociclib.

 

[01:09:50]

 

Summary for Pivotal CDK 4/6 Inhibitor Trials: Overall Survival Findings

 

Now there have been efforts to look - and this is just the same data looked at in a different way, you know, again, are these patients who are postmenopausal? There were trials that looked at premenopausal patients, rendered postmenopausal by GnRH agonist. And again, I'm not going to argue about which one has the best survival benefit or not. I think you can look at the data and judge by your own interpretation of the data.

 

But, you know, we've come to appreciate perhaps ribo and abema are a little bit stronger in that respect in terms of feeling comfortable that there is a survival benefit. But I also say if 1 or 2 of the drugs disappeared off the face of the earth, would you not use the palbociclib, I probably would.

 

[01:10:37]

 

MONARCH-3: Final OS

 

The most recent data with monarchE, which is abemaciclib, is shown here. And again, this shows that there is a significant improvement in overall survival. It fell just short of a statistical benefit. But, you know, I think it's hard to argue that if you look at the median, there is an improvement of basically a year.

 

[01:11:00]

 

MONARCH-3: Postdiscontinuation Therapy

 

It's also important to understand what happened to patients in that trial post progression. And the 1 thing I would draw your attention to on this slide in the far-right column, if you look at the patients who did not get abemaciclib as their treatment, in other words, placebo, most of those are - significant chunk of those patients subsequently got a CD4/6 inhibitor.

 

So when you think about the seemingly improvement of survival of about a year, even though it doesn't reach statistical significance, you have to keep in mind that many of those patients did go on in the placebo group to ultimately get a CD4/6 inhibitor.

 

[01:11:44]

 

SONIA: Timing of CDK4/6i Therapy

 

Now, the other issue that has come up in recent years, and it was driven to a large extent by the Europeans looking at the cost of care. And if you could not necessarily be regimented to give a CD4/6 inhibitor as a first-line therapy. What if you used it second-line? Would the end result be very similar?

 

So the SONIA trial looked at this with either giving endocrine therapy alone or endocrine therapy with a CD4/6 inhibitor as first-line treatment and then at disease progression going on to CD4/6 inhibitor if you didn't get it.

 

And you know, in the first PFS, it's clear that if you got CD4/6 inhibitor, there was a significant improvement in PFS.

 

[01:12:27]

 

SONIA: PFS2 (Primary Endpoint)

 

But if you look at the overall results of PFS2, if you took into account those patients who delayed getting their CD4/6 inhibitor until progression, then you see that the lines are pretty much overlapping.

 

[01:12:43]

 

SONIA: Overall Survival

 

And also the overall survival looks very much the same. Now, from a US centric viewpoint, we would probably say that pushing off progression is in of itself a quality of life metric. Patients feel better if you're not telling me you have to change therapy. And you know, that would be the argument that most medical oncologists in the US would abide by. And that is use whatever you think is most effective upfront and then go on from there. But using this strategy, you sort of get to the same endpoint and the groups look similar.

 

[01:13:18]

 

P-VERIFY: Comparative OS From RW Data

 

There has been an effort to look at real world data or the Flatiron database. There have been a couple of papers trying to readdress the issue of which CD4/6 inhibitor is the best. This is one such publication that was presented at San Antonio last year. And also looked at, you know, a large number of patients in the breast cancer database in Flatiron, some 700,000 patients, and then weaning that database down to - on the far right, you can look at the very bottom and see that you can find 6000-plus patients who got palbo and aromatase inhibitor, 1200 got ribo and aromatase inhibitor and abema and aromatase inhibitor 1000 patients following them out and looking at what the outcome was.

 

[01:14:10]

 

P-Verify: OS

 

And the argument here is, of course, can we find any data that would support the idea that palbo is as good. And looking at real world data, this would suggest that, you know, it's a decent drug. It looks good in this kind of analysis. But if you abide by a randomized clinical trial, it didn't fare as well. But you can look at these data and interpret it as you like.

 

[01:14:35]

 

RIGHT Choice: Ribociclib + ET vs Combination CT in Aggressive HR+/HER2- Advanced Breast Cancer

 

There have been several trials over the last few years that have addressed the question that I thought we knew the answer to. And that is that if you have ER-positive disease, you try and put off chemotherapy. And, you know, the question often comes up and we tell our trainees, you know, you don't have to use chemotherapy just because the patient has a liver met or a lung met. And is there a threshold where you should bypass endocrine therapy and just go to chemotherapy and maybe come back to endocrine therapy later?

 

And there have been several trials now. I’ll just highlight a couple of them looking at the role of chemotherapy vs optimal endocrine therapy. And I pick the RIGHT Choice trial because this was a trial that was presented a couple of years ago that looked at patients, not just with, you know, a couple of mets here and there, but these are patients who are thought to have aggressive disease as defined in the trial.

 

Their bilirubin could have been a little bit up, not too high. And they had no prior systemic therapy. So there was enough on their clinical presentation that made you worry that should these be patients that might benefit more from chemo than endocrine therapy, to the point where the chemotherapy offered was not single-agent chemotherapy but doublet therapy, as you can see in the red box vs optimal endocrine therapy with the CD4/6 inhibitor and endocrine therapy.

 

[01:15:58]

 

RIGHT Choice: PFS (Primary Endpoint)

 

And what the results showed is that endocrine therapy given in an optimal fashion, was better than chemotherapy. And the improvement in PFS favored optimal endocrine therapy by about ten months. So this sort of puts the nail in the thought that you must always use chemotherapy in such a patient group. And there have been other trials that have looked at this as well, coming up with similar results, even using single-agent chemotherapy in older patients like capecitabine or in younger patients where you render in postmenopausal Young-PEARL and the PEARL studies showing very similar results.

 

[01:16:36]

 

ABIGAIL: Phase II Abemaciclib With or Without Induction Paclitaxel in HR+ Metastatic Breast Cancer

 

So what about looking at induction chemotherapy, you know, sort of halfway measure? You're going to give them chemotherapy, but then you're going to pivot immediately to endocrine therapy with a CD4/6 inhibitor. And the randomized phase II ABIGAIL trial looked at this, where patients got paclitaxel sort of as an induction and then after 12 weeks went on to get endocrine therapy. Or they simply started in the other arm with endocrine therapy plus a CD4/6 inhibitor and they continued that therapy until toxicity progressive disease or death.

 

[01:17:13]

 

ABIGAIL: 12-Wk ORR and Safety

 

And what did we see at the 12-week mark? Well, number 1, if you look at the box on the left is the objective response rate again was superior with optimal endocrine therapy vs single-agent paclitaxel—basically 60% vs 40%. And you can see that most of those responses were partial. You weren't seeing a lot of complete responses, which is no surprise. We don't see that with chemotherapy either.

 

And then if you look at the safety profile on the right, again, for the most part, the chemotherapy treatment had somewhat higher risk of toxicity in many different domains. But I don't want to minimize that you can get toxicity when you combine endocrine therapy with a CD4/6 inhibitor, in this case, abema. And you do see a marked uptick in diarrhea as an example, although it's lower grade.

 

So again, we have to pay attention to even some of these lower grade toxicities. And I know Joanne will talk about that as well in terms of how that affects patients’ day to day life and what their - their experience is.

 

[01:18:23]

 

PADMA: ET + Palbociclib vs Standard Chemotherapy in High-Risk HR+/HER2- MBC

 

The PADMA study is also one that looked at a strategy where you are looking at optimal endocrine therapy, in this case with palbociclib vs standard chemotherapy in high-risk patients with hormone receptor-positive disease. So endocrine therapy plus palbo vs physician's choice of chemotherapy followed by endocrine therapy maintenance. And the maintenance could have been with any of a variety of endocrine agents, including GnRH agonist therapy.

 

And again, most of the chemotherapy was given as single-agent either Taxol, cape, epirubicin or vinorelbine. So it was pretty liberal on what you could choose.

 

[01:19:04]

 

PADMA: TTF (Primary Endpoint)

 

And again, there's a consistent finding that using optimal endocrine therapy compared to chemotherapy plus or minus a maintenance endocrine therapy, patients receiving optimal endocrine therapy fared better with respect to the endpoint of time to treatment failure.

 

[01:19:21]

 

PADMA: PFS and OS (Secondary Endpoints)

 

And if you look at the other endpoints, PFS 18 months vs 7 months overall survival, again a randomized phase II. It's not definitive. But you see the same trend 46 months vs 36 months. So a consistent finding across several different experiences that using optimal endocrine therapy can trump using chemotherapy, whether you use it alone or in sequence with endocrine therapy.

 

[01:19:49]

 

MAINTAIN: Switching ET ± Ribociclib for HR+/HER2- mBC After Progression on Previous ET + CDK4/6i

 

Now, pivoting a little bit to the question of can you use sequential CD4/6 inhibitors? There have been several trials now that have addressed this issue, MAINTAIN, postMONARCH and others. And what I would sort of jump to the conclusion before I show you a couple of the data sets, is there is a signal that you could do this in select patients, particularly if you don't have another target that you identify with NGS testing. So if somebody has progressed on a CD4/6 inhibitor, particularly if they had a long duration of benefit from whatever CD4/6 inhibitor they were on, one could make the decision to try either switching out the endocrine therapy or switching the CD4/6 inhibitor.

 

So in the MAINTAIN trial, patients who had progressed on an endocrine agent plus a CD4/6 inhibitor largely, palbo, or randomized to ribo with a switch of endocrine therapy. So 2 things are changing, or placebo, plus a switch of the endocrine therapy alone.

 

[01:20:54]

 

MAINTAIN: PFS

 

And again, there was a signal suggesting that there might be a modest improvement with that switch. You can see the median one from just shy of 3 months to just a little bit above 5 months. So you could say 2-month improvement, 8 weeks. The fraction of patients without progression at 6 and 12 months was greater in MAINTAIN if you went on a sequential CD4/6 inhibitor.

 

But I think we've seen more benefit if you have a different target that you could use. So PI3 kinase mutation, you could use an inhibitor there, ESR mutation. But again for select patients this could be a consideration.

 

[01:21:31]

 

          MAINTAIN: Responses

 

You see a little bit greater response and clinical benefit in the switch patients who got the second CD4/6 inhibitor. But again it's a signal.

 

[01:21:42]

 

postMONARCH: Abemaciclib + FULV vs FULV for HR+/HER2- ABC After Progression on CDK4/6i + ET

 

postMONARCH too address this issue. These were patients who had progressive disease on first line CD4/6 inhibitor therapy. Again, it was a mix but largely palbo and then at disease progression, went on to abemaciclib plus fulvestrant or fulvestrant alone.

 

[01:21:57]

 

postMONARCH: PFS

 

And if you look at the data from this trial again, a signal. And you know, I guess when I saw this data, you do see improvement. You can look at landmark time points—time points of 6 months, 12 months. More of the patients are without disease progression. Whether you look at the investigator analysis or the BICR blinded. Again, there seems to be an advantage with the switch. But I would make the case that it's probably fairly modest.

 

[01:22:26]

 

postMONARCH: PFS in Biomarker-Evaluable Patient Population

 

And you can look at subsets in that population, whether they had ESR mutations, yes, no. PI3 kinase, AKT, PTEN pathway abnormalities. Again, most of the data - small - small numbers would suggest that you get a benefit switching to abema on that experience.

 

[01:22:43]   

 

CDK4/6 Inhibitors: Postprogression Trials

 

So there are trials that have looked at this, including ones that I didn't talk about, including the PACE trial, which included an immunotherapy treatment arm in addition to the fulvestrant and the CD4/6 inhibitor. But at present, I wouldn't put my money on this as a going to confer a big benefit for most patients.

 

[01:23:03]

 

PADA-1: Switching to Palbociclib + Fulv vs Continuing AI Therapy in ER+/HER2- MBC With Rising ESR1 Mutations  

 

Now we're going to hear about SERENA-6. I think you're all familiar with that. The trial that preceded that, that really laid the groundwork for that in many ways is PADA-1. PADA-1 is shown here. These are patients with metastatic disease who were treated with an aromatase inhibitor and a CD4/4 inhibitor, palbociclib.

 

They were monitored for the emergence of an ESR mutation. And if it occurred, they were switched if there was no evidence of disease progression, radiologically to fulvestrant-palbo or continued on aromatase inhibitor plus palbo. So an early switch based on a molecular change.

 

[01:23:42]

 

PADA-1 Update: PFS From Randomization (Primary Endpoint)

 

And what the data demonstrated was that there was an improvement in PFS with that switch. And again, to build on that experience, we'll see the SERENA-6 data coming up in the next couple of days.

 

[01:23:54]

 

PADA-1 Update: PFS2 From Randomization

 

And the second, PFS2 from randomization also favored that switch as well.

 

[01:24:04]

 

EMBER-3: Imlunestrant ± Abemaciclib vs SoC ET in Patients With ER+/HER2- ABC After Progression on ET

 

And then finally looking at some of the more recent data that represents the newest stuff with SERDs, the EMBER-3 trial, which we heard about at San Antonio by Komal Jhaveri, you know, in December looked at imlunestrant as monotherapy or imlunestrant plus abemaciclib or standard of care endocrine therapy. And these were patients who had progressed on or after an aromatase inhibitor plus or minus a CD4/6 inhibitor. You've seen these data before.

 

[01:24:34]

 

EMBER-3: PFS for Imlunestrant + Abemaciclib vs Imlunestrant (A Primary Endpoint)

 

If you look at the monotherapy arm, the patients who benefited in the monotherapy arm were only those that harbored a ESR1 mutation. If you look at imlunestrant plus abéma vs imlunestrant alone, the primary analysis not even teasing out who had ESR mutations, the patients who got the combo did much better 9.4 vs 5.5 months, which was significantly better.

 

And what I'm not showing you is that if you look at whether they had an ESR mutation or not, that combo was better, but only with monotherapy would you see a benefit in those that have an ESR1 mutation.

 

[01:25:19]

 

PATINA: Addition of Palbociclib to Anti-HER2 Therapy + ET vs Anti-HER2 Therapy + ET in HR+/HER2+ mBC

 

And then probably the biggest thing that - the other big thing that came out of San Antonio, of course, was in patients who are both HER2-positive and ER-positive. And what do we do with those patients?

 

If you look at PATINA, these were patients who had HER2-positive disease, treated as we would typically treat a patient with HER2-positive disease, chemo, trastuzumab pertuzumab. They come off the chemotherapy. If they don't have a - they don't have evidence of disease progression. They were randomized to continue trastuzumab pertuzumab with endocrine therapy or the addition of the same with palbociclib.

 

[01:25:59]

 

PATINA: PFS

 

And as you know from that data set—I'm just going to skip to it. There was a significant improvement in PFS with the addition of palbociclib. It went from 29 months to 44 months. So targeting both pathways, optimizing endocrine therapy as well as continuing optimal HER2 therapy conferred a benefit.

 

And even this afternoon, in the metastatic disease setting, we heard a couple of trials that are sort of thematically in this area as well.

 

[01:26:30]

 

Posttest 2

 

So with that, I'll come to the post-test question. How confident are you in your ability to select CD4/6 inhibitor therapy for your patients with metastatic disease based on current guidelines and evidence? You can read it.

 

1. Not confident;
2. Low;
3. Modest;
4. Confident;
5. Very confident.

 

Okay, we're at least kind of going in the right direction. That's good. It's always bad when you go the backwards. It makes you feel bad. All right. Okay.

 

Okay. Dr Mortimer.

 

[01:27:22]

 

Managing AEs and Promoting Adherence and Persistence With CDK4/6i

 

Dr Mortimer: Okay. I want to thank Bill and Heather for setting the background for the benefits of CDK4/6 inhibitors, not only in the metastatic disease setting, but in the adjuvant setting. And these drugs are very important. But of course they only work if you actually take them. And so managing side effects to ensure that patients stay on them is incredibly important.

 

[01:27:50]

 

How We Identify Side Effects of Therapeutic Agents

 

So let me start out by talking about how we identify side effects in therapeutic trials, because this really is a perpetually moving target.

 

Initially, we identify side effects based on registration trials. And by necessity, the patients who are enrolled on these trials are generally patients who are in pretty good shape. But as those drugs get approved, as we expand to use them in patients with who are older, who have comorbidities, we need to identify toxicities from the real-world experience.

 

The FDA helps us identify additional toxicities and using the Adverse Event Reporting System, which both patients and physicians can identify toxicity through.

 

But again it's important to know that this is a moving target because 30% of newly approved drugs face safety concerns after their approval. And I'll talk about that in more detail.

 

[01:28:42]

 

Why Is Understanding Toxicity Important?

 

It's important to understand toxicity because it helps us to understand the biologic mechanisms of the drugs that we're using. It identifies other potential indications. Certainly the CDK4/6 inhibitors are being used in other primary cancers. But it's important to understand toxicity to keep the patient on study, because we may need to change the dose and schedule in order to keep compliance and effective therapy.

 

And lastly, toxicity. Sometimes the cost of managing it may increase the expense of the treatment.

 

[01:29:16]

 

Patient Case 2: Woman With MBC on Palbociclib With Neutropenia

 

So this is our first case, a woman with metastatic breast cancer who is on palbociclib. She has stage IV disease involving bone and liver. She's on full dose palbociclib 125 mg daily. And she is seeing you in follow up today. She notes that she is fatigued but otherwise stable, and she's going to start her next cycle of palbociclib tomorrow.

 

Her CBC shows that her white count is 1.5, her hemoglobin and platelets are normal, but on her differential her ANC is 560.

 

[01:29:49]

 

Poll 4

 

So in practice what would you recommend for this patient?

 

1. Continue current therapy;
2. Stop the palbociclib and switch to abemaciclib;
3. Administer growth factor and resume palbociclib at a lower dose when the ANC gets to 1000 or over;
4. Initiate prophylactic antibiotics. Hold the palbociclib dose until the ANC is 1000 or more, and then resume palbociclib at a dose of 100 mg; or
5. Hold the palbociclib dose until the ANC recovers or resume palbociclib at a dose of 100 mg.

 

Okay. So most of you would hold the palbociclib until the ANC is 1000 or more, and then resume it at a lower dose.

 

[01:31:07]

 

Dose Modification and Management for Neutropenia

 

Okay. So this is right out of the package insert. And - and most of you got the correct answer. Having a granulocyte count of 1000 or more is really important. And if the patient at the start of their next cycle has more than 1000 granulocytes, you don't need to change the dose. If, however, they have a grade 3 less than a 1000, you need to interrupt the dose until they recover and then give them another challenge at the same dose if they have - if they recur again, then reduce the dose.

 

If the patient is febrile, however, or has a grade 4, then you need to dose/redose without giving them a second challenge.

 

[01:31:46]

 

Roadmap for Managing Hematologic Toxicity With CDK4/6 Inhibitors

 

This slide just summarizes a recent review of a roadmap for managing hematologic toxicity in the CDK4/6 inhibitors. So with severe neutropenia, that is grade 3, withhold the CDK4/6 inhibitor, wait for spontaneous recovery, resume at the next lower dose level. And the package insert, they would - they would actually recommend a challenge first, a second challenge.

 

G-CSF support is not indicated. With persistent neutropenia, especially if it's associated with anemia or thrombocytopenia, you should be worried that they may have a myelophthisic process, and consider a bone marrow biopsy to rule out marrow involvement and antibacterial prophylaxis is not indicated as a risk of infection is extremely low, and I think we're always surprised at how often people are cytopenic but never get infected with these agents.

 

[01:32:35]

 

NATALEE and monarchE: Tolerability and QoL

 

So compliance is not so much a problem in metastatic disease. Patients are - are on drugs and they know whether they're working or not. Where compliance really becomes a challenge and why managing toxicity becomes more and more challenging is - is in the adjuvant setting because patients are on drugs they hope are working, but they have no objective evidence that they are.

 

So let's look at the toxicity, the grade 3 or more toxicity in the NATALEE trial. 44% of patients had neutropenia, 8.6% liver-related adverse events and 1% a QTc interval prolongation.

 

And monarchE, the major side effects were largely diarrhea. 19% of patients had granulocytopenia and 3% had liver adverse events. But the biggest problem on monarchE is, of course, diarrhea with abemaciclib. Well, this is grade 3 toxicity or more. Somewhere between 80% and 90% of patients have some degree of diarrhea and abemaciclib.

 

[01:33:45]

 

monarchE: Abemaciclib Discontinuations

 

So if we look at monarchE, more than half of the early discontinuations due to adverse events occurred within the first 5 months. And on the right, you see that those adverse events were - were variable, 5% were diarrhea, 1.9 fatigue, and a small percent were neutropenia.

 

Managing the diarrhea with abemaciclib continues to be challenging on a regular basis.

 

[01:34:10]

 

Patient Case 3: Woman on Adjuvant Abemaciclib With Diarrhea

 

And I'm going to present a case of a 55-year-old with a T2N1 tumor. And she's been on abemaciclib for 2 months. And she calls because she now has 6 to 8 episodes per day of diarrhea that are difficult to predict despite taking the as needed antidiarrheal medication. She says her weight is stable and that she's eating and drinking without problems.

 

She notes fatigue despite adequate sleep and is having trouble returning to work as a result. So you ask her to hold abemaciclib until her symptoms resolve.

 

[01:34:46]

 

Pretest 3

 

So what additional counseling would you provide for this patient?

 

1. She should restart abemaciclib with no change to dose or schedule and increase the use of anti-diarrheal medication;
2. She should restart abemaciclib with a dose reduction and continue antidiarrheals as needed;
3. She should switch from abemaciclib to ribociclib due to the emergent toxicity; or
4. She should stop adjuvant CDK4/6 inhibitor and continue on endocrine therapy as monotherapy.

 

Okay, so most of you just thought, she should restart it with the dose reduction and continue antidiarrheals as needed.

 

[01:35:42]

 

Characteristics of Diarrhea With Abemaciclib From Real-life Data (N = 80)

 

It's been hard to sort of sort out who—how the diarrhea—what the symptoms are because it's variable. And - and also who is at risk for them? Because it's not obvious, but this is a very small study that looked at diarrhea associated with abemaciclib in 80 patients.

 

And what they identified was that the risks of age greater than or equal to 70 years, polypharmacy, those with East Asian heritage, those that had concomitant or prior intestinal diseases. There was no association with fiber rich diet or laxative use previously.

 

And the characteristic of the diarrhea was usually loose, watery, frequent stools, and it generally peaks within the first 3 cycles and tapers off, and that may just be a function of modification or dose or schedule.

 

[01:36:30]

 

Management of Abemaciclib-Induced Diarrhea

 

So these are the guidelines for managing abemaciclib-induced diarrhea. So at the first sign of loose stools patients are to initiate antidiarrheals like loperamide. And they're encouraged to increase their fluid intake. Those patients who have less than 4 stools a day should continue on abemaciclib without dose modification.

 

Those patients who have 4 to 6 stools a day should hold the abemaciclib until they resolve to grade 1, and then may choose to have no dose modification and give them another challenge or reduce the dose.

 

Grade 3, which is 7 or more stools a day, should hold the dose until it resolves and reduce the dose. Often may discontinue the abemaciclib, but they're unable to tolerate doses as low as 50 twice a day. So patients are always encouraged to have low fiber, low fat, small, frequent meals. But - but in truth, there really is no clear data that this actually helps abemaciclib-induced diarrhea. That's sort of nursing management of diarrhea in general.

 

[01:37:34]

 

Patient Case 3: Woman on Adjuvant Abemaciclib With Diarrhea

 

So let's go back to the case of the patient with diarrhea.

 

[01:37:41]

 

Posttest 3

 

And what is the - what additional counseling would you provide for this patient as the most appropriate next step for her treatment? So most of you - oops, sorry. We did this.

 

[01:38:28]

 

Posttest 3: Rationale

 

Okay, so the correct - the correct answer is that she should restart abemaciclib with a dose reduction and continue antidiarrheals as needed because she has grade 3 toxicity. And - and so continuing the antidiarrheals is, of course, appropriate. And - but the abemaciclib dose should be reduced.

 

[01:38:46]

 

Patient Case 4: VTE With Abemaciclib

 

So another side effect of ribociclib which is unique to ribociclib is that of hepatotoxicity.

 

[01:38:55]

 

Monitoring and Management of Ribociclib-Induced Hepatotoxicity in Advanced Breast Cancer

 

So when we start a patient on ribociclib, we get baseline liver function tests, and - like the other CDK4/6 inhibitors. And we also get a CBC and QTc at baseline every 2 weeks for 2 full cycles.

 

So when you do this, you look for toxicity - liver toxicity and the basis of AST and ALT elevations from baseline. And they cannot have a bilirubin increase above 2 times the upper limit of normal.

 

For patients who have less than 3 times the upper limit of normal in their transaminases, there's no need for a dose reduction. For 3 to 5, we need to hold the dose until the liver function tests resolve and then resume at the same dose of ribociclib. If it recurs, then resume at the next lower dose.

 

For patients who have grade 3 somewhere between 5 and 20 times the upper limit of normal, you want to hold the dose until it resolves to less than a baseline grade and resume at the next lower dose level, or if it recurs again, to permanently discontinue. And patients who have grade 4 should have permanent discontinuation of - of ribociclib.

 

I have to say these are the guidelines. It's very anxiety provoking when patients liver function tests go up. So I would have to say, personally, I have a tendency to quit and switch to a different CDK4/6 inhibitor rather than run the risk of causing hepatotoxicity.

 

[01:40:26]

 

Patient Case 4: VTE With Abemaciclib

 

So another case of toxicity is - is venous thromboembolism. And this is a 49-year-old teacher who had a locally advanced hormone-positive/HER2-negative breast cancer. She got dose dense AC followed by Taxol and had residual disease. And she's now on abemaciclib and letrozole from June 2023. And 9 months later, she presented with a swollen left calf, shortness of breath and was found to have a deep vein thrombosis and a segmental and subsegmental bronchial pulmonary embolism.

 

[01:40:57]

 

Real-World Studies vs Clinical Trials: VTE and Arterial Thromboses

 

This is where the real world toxicity data is incredibly important. In both the first-line studies of PALOMA-2 and MONALEESA-2, patients who had cardiovascular disease, and within the past 6 or 12 months prior to the entry in study, were considered ineligible. And so there was a low incidence of venous thromboembolism.

 

So if we look at venous thromboembolism on the left according to clinical trials, do you see that the incidence is very low. It's present for all 3 CDK4/6 inhibitors. But when you add to it the real world data, the number - the percentage of venous thromboembolism significantly increases.

 

Arterial thrombosis also occur. And again in the - in the clinical trials, the registration trials, this was very uncommon. But in the real world data, it turns out that there is a predictable incidence. Although both VTEs and arterial thrombosis do seem to be somewhat less in the ribociclib patients.

 

[01:42:05]

 

Thrombotic Events in Patients on CDK4/6 Inhibitors Summary

 

So I think to summarize, these thromboembolic complications occur with all 3 agents. It may be slightly lower with ribociclib. It may be related to concurrent use of tamoxifen in monarchE. 30% of patients were - were receiving tamoxifen.

 

It's unclear the relationship to concurrent cardiovascular disease. We can presume this is an increased risk, but these clots may be both venous as well as arterial. And some of these events have been fatal.

 

[01:42:34]

 

Monitoring, Managing and Mitigating VTE With Abemaciclib

 

So patients who are treated with CDK4/6 inhibitors. And this says abemaciclib because it was the first one to get a black box warning for clots, we need to monitor them for signs and symptoms of PE and thrombosis and treat as medically appropriate. And patients should or should be advised to report their signs and symptoms.

 

In terms of treatment, there's very little guideline for how to treat these patients. Any grade you should suspend it and treat them with clinically indicated. The patient that I presented went on apixaban, and she completed her 2 years of abemaciclib without any further complications.

 

[01:43:13]

 

QTc Prolongation With Ribociclib and Dose Modifications

 

I'm just going to quickly mention QTc prolongation, which are uniquely attentive in patients on ribociclib. And the cutoff is 480 milliseconds. So if at baseline in those every-2-week intervals, you find somebody whose QTc is elevated, you need to interrupt ribociclib and wait until the QTc returns to normal. And if it continues, then you need to consider switching to a different agent.

 

[01:43:40]

 

Mean Monthly eGFR for the First Year of CDK4/6i Treatment Compared With Aromatase Inhibitors Alone

 

I'm going to talk about renal toxicity, which is really not a toxicity associated with abemaciclib, but is worth noting about. This is a study that looked at patients with metastatic breast cancer. 474 women who were treated with endocrine therapy alone or with palbociclib and abemaciclib concurrent.

 

And as you see, the elevations in GFR. We're seeing really predominantly in - in the abemaciclib treated patients.

 

[01:44:09]

 

Renal Toxicity With Abemaciclib: Mechanisms of Action

 

And this is important to note because abemaciclib does not cause renal toxicity. What it does do is it interferes with the transport of creatinine from the blood into - into the urine. And by blocking those transport mechanisms with abemaciclib you end up with a higher level of serum creatinine. So it's artificially elevated. And it can be artificially elevated by as much as 20% or 30%. So it's not a toxicity, but it does cause elevations in serum creatinine.

 

And if you want to know somebody's serum creatinine use an alternative method of assessment.

 

[01:44:49]

 

76-Yr-Old With Stage IV HR+/HER2- IDC

 

So this is a 76-year-old woman who had stage IV disease. She was one of the first patients I treated with palbociclib. And 5 months after being on palbociclib and fulvestrant, she developed shortness of breath, and she went another 2.5 months before she was significantly hypoxic, and her O2 sat was 83% with walking.

 

And this demonstrates what you see on CT scan. And she has those ground glass opacities which - which drive us crazy on our scans these days. And her tumor was responding otherwise. So this was the first case that I saw of - of interstitial lung disease, which we reported.

 

[01:45:30]

 

Meta-analysis of CDK4/6 Inhibitor-Associated Interstitial Lung Disease

 

So interstitial lung disease usually presents as a cough, shortness of breath and abnormal x-ray. There are 12 randomized studies that have 16,000 patients, most of whom had breast cancer. And the incidence of interstitial lung disease is about 1.6% in the arms that get a CDK4/6 inhibitor, compared to 0.7 in the control.

 

And when you look at the FDA adverse event log, abemaciclib may be slightly more common than patients who are on ribociclib or palbociclib. The median latency is 50 days for abemaciclib, and ribociclib 253 days.

 

[01:46:09]

 

Roadmap for Managing ILD With CDK4/6 Inhibitors

 

So the recommendations from this roadmap group are to get a CT to consider a bronch. If it's grade 1, no intervention is necessary and no dose modification. But if it's a grade 2, you should institute prednisone until symptoms decrease to a grade 1 and then consider resumption when symptoms resolve.

 

If it's grade 3 or 4 requiring hospitalization, the CDK4/6 inhibitor should be stopped and steroids initiated. Know that these are sort of mutually exclusive. Some patients who have interstitial lung disease, when they switch to a different CDK4/6 inhibitor, will tolerate the drug without development of interstitial pneumonitis.

 

[01:46:47]

 

Skin Toxicity With CDK4/6 Inhibitors

 

So the last toxicity I want to talk about is skin toxicity. And these are obviously not stock pictures. These are the pictures our patients send us constantly through the portal and emails. She's 76 and had been on ribociclib for 4 months with concurrent letrozole and developed a rash. And she was a total body rash, was treated with steroids, and subsequently switched to abemaciclib with continued efficacy and without further eruptions.

 

[01:47:13]

 

Alopecia With CDK4/6 Inhibitors

 

Alopecia is a consistent side effect that we see when we add CDK4/6 inhibitors to endocrine therapy. And as this 55-year-old woman demonstrates, you see it largely in the top of her head. A retrospective trial of 28 women who had breast cancer and were on endocrine therapy, with or without a CDK4/6 inhibitor, sort of showed that this vertex involvement was much more common with CDK4/6 inhibitor. And interestingly, they had a worse response to minoxidil than those women who had endocrine therapy alone.

 

[01:47:46]

 

Skin Toxicity With CDK4/6 Inhibitors

 

And this is a 49-year-old patient who is on abemaciclib and developed, vitiligo, and it took me a while to realize that this really was from her abemaciclib. This has been reported with - with all of the CDK4/6 inhibitors. She is now on a different CDK4/6 inhibitor. Her vitiligo has not resolved, but she has not developed worsened.

 

[01:48:11]

 

Key AEs With CDK4/6 Inhibitors: Monitoring and Prevention to Maximize Adherence

 

So to summarize the side effects. Diarrhea is predominantly a side effect that we have to deal with, with abemaciclib. We use antidiarrheal therapies, but modification in - in dose is - is often required.

 

Hepatotoxicity can occur with abemaciclib. It is especially concerning in ribociclib, and that's why we need to consistently measure liver function tests at baseline and every 2 weeks for 2 full cycles.

 

Neutropenia is a side effect of all 3 CDK4/6 inhibitors, and we went over those guidelines in the first case. Venous thromboembolism occur with all 3 as well. And patients should be aware of this as a potential side effect, and we need to monitor them for signs of thrombosis and emboli.

 

And interstitial lung disease, though not common, does occur with an incidence of around 1 to 2%, and we need to make sure that patients are monitored for pulmonary symptoms that are indicative of interstitial lung disease.

 

[01:49:14]

 

Key AEs With CDK4/6 Inhibitors: Monitoring and Prevention to Maximize Adherence

 

I didn't talk about fatigue. Patients complain about fatigue always, and this continues to be a problem for all of us in whatever systemic therapy we're - we're administering. And really, to be fair, only exercise is really clearly been shown to demonstrate an improvement in fatigue with sort of chemotherapy induced fatigue.

 

Elevated creatinine is not a side effect of abemaciclib. It is elevated because of interference with the measurement of serum creatinine.

 

And lastly, skin reactions occur with all 3 CDK4/6 inhibitors.

 

[01:49:50]

 

33% of Newly Approved Drugs Faced Safety Concerns After Approval

 

So I started out by saying this is a perpetually moving target, that this really is a dynamic process of identifying toxicities associated not with the CDK4/6 inhibitors alone, but with all drugs. And if you question that, let's think about tamoxifen, which was approved in 1977. And it took the chemoprevention trials to raise the possibility that cataracts were increased in patients who were treated with tamoxifen.

 

And it took several decades before we realized that, in fact, endometrial cancer was at increased risk in women who were taking tamoxifen.

 

As we look at toxicity, we always start with patients with metastatic disease, and attribution of toxicity is somewhat more complicated then because these patients have symptoms. And so when the aromatase inhibitors were first brought out in metastatic disease, we probably missed the fact that musculoskeletal complaints were not due to bone metastases. But now in the adjuvant setting, we realize that this is a completely unique syndrome to aromatase inhibitors.

 

And lastly, bisphosphonates. So all 3 of these agents we use regularly. Bisphosphonates first were found to be effective in treatment of bone metastases in 1989. But it took 20 years for us to realize that osteonecrosis of the jaw was a complication of bisphosphonate use and - and as well as atypical femoral fractures, and not just with oncologic patients, but with patients with osteoporosis treated with oral bisphosphonates as well.

 

[01:51:27]

 

Poll 5

 

So let me conclude by saying, do you plan to make any changes in your clinical practice based on what you learned in today's program?

 

[01:52:01]

 

Poll 6

 

Okay. And please take a moment to text in one key change that you plan to make in your clinical practice based on this education today.

 

Next one is yours.

 

Dr Gradishar: All right. Thank you very much. So...

 

Dr Mortimer: Thanks.

 

[01:52:35]

 

Q&A

 

Dr Gradishar: So we have a few minutes for questions remaining, both from the virtual audience as well as the one in this room. There have been some that have come in online. And feel free if you want to ask a question. We can just get up and ask it.

 

But there was 1 question that came in that you addressed in complete sense about renal toxicity. So I don't think we're going to revisit that. There is a question about, if a patient is tolerating abemaciclib and a nonsteroidal aromatase inhibitor - I'm presuming this is in the metastatic disease setting - can they stand this regimen if the disease does not progress indefinitely?

 

Well, I guess if somebody's got documented metastatic disease, their disease is stable or responding. And equally important, they're tolerating it, then I'm not sure I would necessarily stop it. Of course, the caveats are if they're not tolerating it, that would be a different issue that you might pull back on the CD4/6 inhibitor or you may stop it.

 

And I know 1 of the things we didn't really show. But in the adjuvant trials or in any of the trials where dose reductions were looked at in relation to benefit, it didn't seem like benefit was necessarily attenuated when you had to drop back on the dose. I don't know if either one.

 

Dr McArthur: Yeah. So people who had dose reductions experience signals - people who had dose reductions had the same benefit as those who were maintained on dose, and also older patients who had dose reductions derived the same benefit as patients who were maintained on dose. So you should absolutely not abandon CDK4/6 inhibitor in older populations without exploring dose reductions.

 

I have a question, if I may, because I think this is a struggle and I'm interested to hear, where you are both positioned, adjuvant bisphosphonates because you touched on that Joanne, are endorsed by the ASCO guidelines. And we have no idea what additional risk reduction is conferred in the adjuvant setting beyond CDK4/6 inhibitors. So I'm just curious whether you're both still advocating for adjuvant bisphosphonate use in that high-risk population. You're already giving chemotherapy, hormone therapy, CDK4/6 inhibitor therapy.

 

Dr Mortimer: So for right or for wrong I still do it. I presume there's an added benefit, but since we don't have data to that, you can't say that. But we do know that the addition of bisphosphonates does improve the - the - the - the T score in patients. And presumably that has some benefit long term.

 

There was no - in - in the adjuvant trials of bisphosphonates, there's no real decrease in the incidence of fractures. And for a drug to be approved in the osteoporosis setting, it has to demonstrate decreased fractures. So although the T score increases and relapse free survival was - was improved, there was no decrease in - in fractures in patients on adjuvant bisphosphonates. But I'm assuming they're additive.

 

Dr Gradishar: And the only thing I would say is that in the highest risk patients we do, do that because we're already adding, you know, a CD4/6 inhibitor because we think they're at high risk. So we're trying to - but I would also acknowledge we don't know because the data with CD - I'm sorry. The data with bisphosphonates was generated with monotherapy endocrine therapy.

 

Okay. There's another question on does the - this I'll send to you. Does the duration of ribociclib vs abemaciclib in the adjuvant setting influence you in any way? Is there a patient type where you're more likely to choose one or the other - over the other based on duration?

 

Dr McArthur: It - it does. And I guess because adjuvant abemaciclib came to market first before ribociclib, we were already using that and we were comfortable in getting patients through that 2-month period. And if you're educating them and getting them through the diarrhea, they tend to do well in the long term.

 

That being said, I had a patient on the monarchE study who was very high functioning and who couldn't go to work anymore on adjuvant abemaciclib. So I think there are very nuanced, experience and nuanced conversations. I would rather give 2 years of CDK4/6 inhibitor than 3 years. But that being said, they are very much tailored conversations based on comorbid conditions, based on prior history, based on issues with prior chemotherapy, because presumably you're talking about chemotherapy treated population, etc.. So I don't think it's very black and white and I think it's very nuanced.

 

Dr Mortimer: You know, there certainly are patients who could take abemaciclib who seem to have no significant toxicity. Now, whether that predicts for benefit or no benefit, I guess we don't know. But certainly there are people who are absolutely miserable on abemaciclib. And the concept that giving them antidiarrheals helps. It's not always the case.

 

I mean, this watery diarrhea, this painful defecation that people have is pretty unique and - when they have it. And it's - and it's not going to be resolved by being on a high fiber diet and using antidiarrheals. And so those patients really have a miserable quality of life. And they don't go out, they don't eat when they go out. And they - you know, I think we all have patients like that. So for those folks that are really miserable, giving them abemaciclib is - I mean, having an option of giving them a ribociclib in the adjuvant setting is really appealing.

 

You know, Lilly has a program where the nurses can call the patients and talk to them on a regular basis. And I think the patients really like that because they feel listened to. But I don't think that the interventions are actually very effective. People have done studies with abemaciclib, with probiotics, and they've been negative. So the mechanism is unique. It is the off target effect on CDK9, which - which is a repair gene.

 

And so when you block it for cells that are rapidly dividing, you - you kind of lose the mucosa of your intestines. So this is a really significant problem that can't be under - underestimated in a certain population of people who have it and would make me use ribociclib.

 

Dr Gradishar: Okay. Thank you.

 

Dr McArthur: And I would say just nice that we have options right in our high-risk ER-positive patients in the adjuvant setting.

 

Dr Gradishar: Okay. It looks like we have time for 1 quick question. Any thoughts on why palbo didn't seem to have a benefit in the adjuvant setting?

 

Dr McArthur: So I think in part, I don't think it's a drug effect necessarily. I think it's the - it was the ANC issue. And so in the monarchE, for example, you could adjust for symptoms based on diarrhea, for example - based on diarrhea, for example, with abemaciclib. But with palbociclib, they had very strict hold and discontinuation parameters based on ANC, which you can't, like manage in the adjuvant setting. It's not - they're not clinical symptoms.

 

So I think that in part was and maybe not entirely, but in part was an issue. And it's interesting to see the resurrection, though of palbociclib with PATINA, which was mentioned earlier because that has become an interesting option now in that maintenance setting with the 15-month PFS improvement, which I think shocked many of us. But I - I think it was a clinical management of symptoms vs trying to manage lab result issues.