This transcript was automatically generated from the video recording and may contain inaccuracies, including errors or typographical mistakes.

Translating Evidence Into Practice: Optimization of CDK4/6 Therapy in HR+/HER2- EBC

What Is “High Risk” in HR+/HER2- EBC?

We will start out by defining what is high-risk? We know that patients with HR+/HER2- early breast cancer have the highest risk of recurrence within the first two to three years after their diagnosis. If you look at the chart to the left here, stage III has a much higher risk of this recurrence. Eventually, after that two to three-year period, things plateau but their risk never really goes to zero.

We do not have a specific definition of what exactly makes a patient high-risk, but we know that things like a larger tumor size, node-positivity, higher grades, and things like a higher Ki-67 index likely play a role.

Risk of Distant Recurrence After 5 Yr of Endocrine Therapy

To demonstrate what that nodal positivity does to your recurrence risk. You can see here that patients who have four or more positive lymph nodes, so the red line on this chart. After about 20 years, they have over a 50% chance of having a distant recurrence during that time because of those positive lymph nodes.

Distant recurrence, obviously we know at that point patients are no longer curable. So definitely a need that is unmet at this time.

Treatment of HR+/HER2- EBC

In terms of the overall treatment paradigm for this patient population. If you have positive lymph nodes, you are likely receiving chemotherapy. We can also use things like genomic risk profiling and Oncotype DX or MammaPrint to determine benefit of utilizing this, certainly in our node-negative patients. Endocrine therapy is really the backbone of our adjuvant treatment.

Obviously, drugs like tamoxifen and aromatase inhibitors have been around for a while. We know that aromatase inhibitors in general outperform tamoxifen in decreasing that risk of recurrence.

We also utilize ovarian suppression in our patients who are premenopausal, certainly if they are receiving aromatase inhibitors. We can use this for five to 10 years. Again, we have this unmet need where patients are still recurring.

Adjuvant EBC Trials With CDK4/6 Inhibitors

A treatment modality that has been investigated to try to decrease this risk of recurrence is the addition of CDK4/6 inhibitors to endocrine therapy. Palbociclib has been studied in this setting with the PENELOPE-B and PALLAS trials. We would not go into detail related to these, but I will say that their primary endpoint of iDFS for either a year or two years of palbociclib was not statistically significant.

We are going to focus on the monarchE and NATALEE trials that investigated abemaciclib and ribociclib in this setting for either two to three years.

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

First up, we will talk about monarchE, which was adjuvant abemaciclib with endocrine therapy for high-risk node-positive HR+ patients.

Now patients were divided into two cohorts. The majority of patients were in cohort one, which were patients who had four or more positive axillary lymph nodes, or one to three positive lymph nodes with an additional risk factor, such as histologic grade 3 disease or tumor size greater than or equal to five centimeters. Smaller population of patients were included in cohort two, which were one to three positive lymph nodes, and then the only high-risk factor they had was a higher Ki-67 index.

Patients were randomized to abemaciclib 150 milligrams BID up to two years with endocrine therapy versus endocrine therapy alone with a primary endpoint of invasive disease-free survival.

monarchE: Sustained iDFS Benefit in ITT at 7 Yr

When this data was initially published, we were seeing at the two-year time frame when patients were stopping treatment that their iDFS benefit was about 2.8%. Now we have most recently seven-year data that shows us that even after patients have stopped treatment, these curves are continuing to diverge. Now the absolute difference is a seven-year rate of 6.5%, which you can see here is statistically significant.

I will point out that this is mostly driven by that cohort one population. Cohort two with the one to three positive lymph nodes and a Ki-67, that was their only risk factor, did not show an iDFS benefit.

monarchE: OS in ITT (Key Secondary Endpoint)

We also have overall survival data at the seven-year time frame that shows a 1.8% absolute benefit in overall survival, which is statistically significant and the first time that we have seen a CDK4/6 inhibitor demonstrate this in the adjuvant setting.

monarchE: Safety

Safety-wise, I will leave that to Rodney to talk about with myth number two. I will just point out here that diarrhea was a significant burden for patients related to abemaciclib and resulted in dosing holds, reductions, and then also discontinuations.

monarchE: Treatment-Emergent AEs of Special Interest

Some other emergent adverse effects of special interest. Of course, we counsel patients in this class of medications on things like VTE risk and also ILD. There was a death related to ILD, so something to point out to patients. We also see some AST and ALT increases here. I will point out the alopecia as well, because this is something I commonly encounter with patients who have just completed chemotherapy. They are excited for their hair to grow back, and they are sometimes seeing alopecia related mostly to the eyebrows and eyelashes. It would be important to point out to a patient when counselling as well.

Approvals and Recommendations: Adjuvant Abemaciclib + ET

As a result of monarchE, we now have an FDA approval for adjuvant abemaciclib in our node-positive patients at high-risk of recurrence. We are really relying on those factors that we see in cohort one to determine who is high-risk. Of note, Ki-67 was initially included in the labelling for this drug and has since been removed. We also see this indication supported by ASCO and NCCN guidelines.

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

Next, we will talk about the NATALEE trial that investigated adjuvant ribociclib with endocrine therapy in an intermediate to high-risk group. Bear with me here. The inclusion criteria are a little bit more complicated. You can see them listed here, but basically stage IIB or III were included. Stage IIA gets a little bit more complex.

If you have node-positive disease, you are included in this group. If you have node-negative disease, you have to then demonstrate an additional high-risk feature, either having grade 3 disease or grade 2 with either a Ki-67 or a high genomic risk profiling. This is something that is not expected to be something that you memorize. But just note that node-negative patients were included.

These patients were randomized to ribociclib 400 milligrams daily, three weeks on, one week off. You will recognize this as our metastatic dosing. However, the metastatic interval that we use for metastatic patients, but the dosing is slightly lower at 400 milligrams as opposed to the 600 milligrams. Patients were given endocrine therapy with an aromatase inhibitor versus aromatase inhibitors alone. Again, primary endpoint here was iDFS.

NATALEE: iDFS

We now have five-year data that demonstrates that at five years our iDFS benefit is about 4.5%.

NATALEE: iDFS in Node-Negative Subgroup

When we hone in on that node-negative subgroup, which, of course, is primary difference between NATALEE and monarchE, we see that the iDFS benefit here also is maintained in our node-negative subgroup and is notably a much smaller population of patients.

NATALEE: DDFS and OS at 5-Yr Landmark Analysis

Distant disease-free survival was also a secondary endpoint, so preventing those distant recurrences where patients are no longer curable. We are seeing about a 4.3% difference here as well.

In terms of overall survival, this appears numerically similar to what we see in monarchE, although we cannot make cross-trial comparisons, but it is not statistically significant of note.

NATALEE: Safety

Safety-wise, we see more neutropenia and also including some cases of febrile neutropenia with ribociclib. We also see some liver-related adverse effects and in practice I definitely see this. It can be LFT elevations, but also some T-bilirubin elevations as well. These can linger over time, sometimes requiring steroids.

Something that is also key with ribociclib is it does cause QT interval prolongation, only in about 5% of patients. But it is required that we do monitoring for it. That includes a baseline QTc that has to be a QTcF of less than 450 in order for the patient to proceed with treatment.

Approvals and Recommendations: Adjuvant Ribociclib + ET

Ribociclib, based on the NATALEE trial, is FDA-approved in this setting for patients with high-risk of recurrence and is again supported by ASCO and NCCN guidelines.

Treatment Algorithm for Adjuvant Targeted Therapy in HR+/HER2- EBC

Because all of those inclusion criteria are so complicated, I have put together a little cheat sheet for you of knowing when to use what. Essentially, you can use this decision tree on the very bottom half of this slide to look at how many positive lymph nodes a patient has, as well as any additional risk factors or comorbidities that you might want to consider to know who is a candidate for one or both of these drugs.

The very top of this slide simply is stating that it is important to consider if a patient has a germline BRCA mutation, because they may be a candidate for an additional adjuvant therapy with olaparib. For the context of this presentation, we would not go through that trial, but it is something to note.

Patient-Specific Considerations

When you have a patient who is a candidate for both, what types of things are we considering? Obviously, their common toxicities are going to be different as well as some of those more rare toxicities.

The endocrine therapy backbone may also play a role in your decision-making. With abemaciclib, we can use any of our oral adjuvant endocrine therapies. With ribociclib, we are limited to our aromatase inhibitors because not only is ribociclib a CYP3A4 substrate like abemaciclib, but it is also a CYP3A4 moderate inhibitor. With that confers many drug interactions. One of those includes tamoxifen and increased risk of QT prolongation.

Also the duration may play a role in shared patient decision-making for two years versus three years. Abemaciclib and ribociclib both include hepatic dosing adjustments, but you will see with ribociclib that it also requires renal dosing adjustments as well.

Myth 1: All CDK4/6 Inhibitors Are Interchangeable in the Adjuvant Setting

Hopefully, we have dispelled this myth number one and now know that all CDK4/6 inhibitors are not interchangeable. The inclusion criteria for NATALEE and monarchE are distinct. The duration of follow-up and having evidence for overall survival with abemaciclib now also makes them distinct.

Of course, we should consider patient-specific factors when we are deciding between the two of them based on the decision points that I have discussed previously.

Posttest 1

Now we will go back to K.H. As a reminder, she is our 33-year-old woman with a premenopausal breast cancer, stage IIIB, and you are asked to explain some of the differences in efficacy to her. In discussions with patients considering adjuvant CDK4/6 inhibitors, which of the following would be accurate to tell them regarding efficacy endpoints for these trials?

We had some improvement from the pre-test. That is great. We have learned something. I would absolutely agree. Both medications reduce that recurrence risk. Abemaciclib is the one that has the overall survival benefit. Both have not demonstrated that overall survival benefit. Then also D may be a little bit of a tricky one, but as we reviewed, once we get past that treatment period, patients are still seeing conferred benefit.

Posttest 2

Now we will go to post-test two. This is our case study on A.F., who is that 42-year-old premenopausal woman who achieved a partial response. Remember she had the seven centimeter tumor initially. She had a 5.2 centimeter tumor initially. She had a positive lymph node. At follow-up, she has a baseline EKG that shows a QTcF of 460 milliseconds.

Which of the following adjuvant CDK4/6 inhibitors is the most appropriate choice for this patient? Let me give you a second to think about this one.

The majority of you actually had this right to begin with. We got in a little more people on the post-test as well.

Posttest 2: Rationale

Important things to consider with this one. Ribociclib, she would have otherwise been a candidate for it, but we got that baseline EKG that showed that her QTc was not within parameters for us to start. That is a really important thing that pharmacists can just nudge to say, “If you are considering both, let us just go ahead and get an EKG to see if they are even a candidate for both of them.”

Palbociclib is not going to be correct because we do not have an indication in this adjuvant setting. Of course, as we reviewed, ribociclib with tamoxifen would not be appropriate for the drug interaction. This patient is also premenopausal. So she would require ovarian suppression with the use of an aromatase inhibitor just of note.

Myth 2: Switching CDK4/6 Inhibitors Is a Preferred Strategy for Toxicity Management

Now I will turn it over to Rodney to discuss myth number two.

Rodney Hunter (Memorial Hermann Medical Center): Thank you, Julia. We learned several things there. We are going to build on that, really talking about toxicity management when we talk about switching from CDK4/6 inhibitors in the early stage breast cancer setting.

Case Study 3

We will start off with another case study. Then we will dive deep into where pharmacists can interact with patients and the clinical team to impact positively these toxicity management that we have to have.

J.C. is a 56-year-old postmenopausal woman with T2N1 disease, HR+/HER2- early stage breast cancer. Completed AC-T, starting letrozole and adjuvant abemaciclib on therapy for 10 days. Her baseline labs are normal at this point, but today she reports three to four loose stools per day above her baseline since day three. She is taking in fluids but not adding any antidiarrheals yet, and her CBC today is at 950 cells, although she is afebrile and appearing well as far as her activity is concerned.

Pretest 3

J.C. is expressing concern about this diarrhea, and I am wondering if her being on it for two years, how that is going to affect her? Beyond the antidiarrheal therapy, what pharmacist-led strategy is most likely to prevent the interruption of therapy?

1. Reassuring the patient that the diarrhea will improve and encourage PRN antidiarrheal use;
2. Counseling the patient and planning a follow-up within 72 hours with diet guidance and escalation criteria;
3. Recommending daily prophylactic antidiarrheals for the rest of therapy; and
4. Pre-emptively holding abemaciclib at the next visit to prevent worsening symptoms.

I definitely got some work to do here. We are pretty much evenly matched at reassuring the patient about diarrhea improving and encouraging PRN antidiarrheals, and also counselling the patient and planning a follow-up within 72 hours with diet guidance and escalation. We will get deeper into that and see maybe what direction we could take to benefit the patient most.

Adherence to Oral Oncology Agents

Okay. Let us start off at the beginning, pharmacists and how we impact the team and how adherence is so important when we talk about CDK4/6 inhibitors, but not only CDK4/6 inhibitors, just oral therapy in general, as we can extrapolate some of the things we are discussing here to any type of oral chemotherapy, with rates being as high as 100% of patients having like a lack of adherence in their therapy.

Women do demonstrate better adherence than men, which is not surprising just considering the species. Also looking at the symptoms of distress, depression, dissatisfaction with the clinical communication. These are all things that can possibly negatively affect adherence.

Reducing adherence is usually directly related to any type of morbidity and mortality. When we think about what we can do as pharmacists and positively affecting adherence, you can see how it is positively affecting the patient's life and we can really get a get a hold of it.

Barriers to Care: Factors Influencing Adherence

Some barriers, and I will speak pretty detailed about these because this is really where we, as pharmacists, come into play a lot of times. Once that decision is made for a therapy to be started on a patient, that is where maybe the physician maybe leaves the room and the pharmacist comes into the room and continues to come into the room every time that patient is coming back to really have these deep conversations about how is the patient doing? What are the things that are barriers that are being caused directly from the patient's perspective. The therapy itself, because I know adverse effects are usually something that can cause patients to have poor adherence, knowing that they take the medication and it always causes them to feel worse than they feel before, which is something I definitely get reported to me in the clinic at times when patients are on oral therapy.

Also disease related, so activity, understanding why they are on the medication, why their duration has been chosen as such. As Julia discussed about the two to three years, depending on which CDK4/6 inhibitor you decide to utilize.

In the healthcare system, how many follow-up visits do you actually get? Do you have to do virtual visits? Can the patient actually talk to a healthcare professional to promote that adherence that we hope to have with the oral therapies?

Then finally, something that actually got a grant from NCI to really look into the social and economic effects on adherence with CDK4/6 inhibitors in my cancer center specifically, and really trying to identify those checkpoints that really are affecting the actual efficacy of the medication when you think about those barriers, like patients being younger or patients being older, patients have a higher out-of-pocket cost, which may possibly affect access to the medication, lower economic status, education level, health literacy and patients having support at home.

Measures to Increase Oral Oncology Treatment Adherence

It is like a multifactorial conversation to talk about oral and oncologic agents in treatment adherence, but these are some things that have been promoted. I always like to talk about the patient really understanding that they are going to have to take a lot of ownership and it is going to be a partnership between you and the patient to get the medication on a daily basis. Or you can build in things like alarms on cell phones, alarm clocks, the smartphone apps. There have been several of them have been studied to see if they positively affect outcomes when you talk about adherence.

Electronic Medical Record is actually something that is really good as well. We also have medication dispensing machines. When you talk about our particular topic today with CDK4/6 inhibitors, I do not think you are putting $13,000 worth of medication in a medication dispensing machine. However, I do think as we move further and further along, when we think about ways to implement change and adherence, there are going to be some artificial intelligence and mechanistic ways like machinery and computers are going to really help patient adherence in the long term.

Patient-Specific Considerations

Going into patient-specific characteristics with CDK4/6 inhibitors. With the abemaciclib, the 150 milligrams twice a day continuously in comparison to the 400 milligrams daily three weeks on, one week off for ribociclib is something to note and something I know that when patients, if they do have to be switched from one to the other, this is always something that we harp on and make sure they completely understand. The neutropenia being something that shows up in both agents, while diarrhea is more prominent versus infection, you could probably say it is more prominent in the ribociclib group.

Also, the QTc prolongation, which Julia discussed, and I will get a little bit more into it as far as dosing consideration is concerned and when to stop, when to start, when to completely discontinue.

ILD shows up in both spaces. Hepatic and hepatic and renal adjustments being something that you can see in both cases with abemaciclib and ribociclib.

Dosing and Schedule Considerations for Adjuvant CDK4/6 Inhibitors

Then as we go further along, you really start talking about things that are permitted. This is always a conversation about the tamoxifen between abemaciclib and monarchE, and then looking at the NATALEE and having the non-steroidal aromatase inhibitors.

The LH/RH agonists are not explicitly listed on the ribociclib group, but you could actually use those in the premenopausal women in the NATALEE trial, so younger and older patients being available to use it.

Grapefruit juice has went out of style. I do not think I have talked to a patient in a while that really likes grapefruit juice. But still having that conversation to make sure if they are that one in million that they avoid grapefruit juice to as far as it can have a 10 to 20-fold increase in the serum concentrations of the both CDK4/6 inhibitors in this case.

Drug–Drug Interactions Among CDK4/6 Inhibitors

Ketoconazole being something you have to explicitly just avoid. You do not have any movement there. If the patient is in need of an antifungal, that is not the one you are going to be able to use. Strong and moderate CYP3A4 inhibitors. There are dosing considerations with abemaciclib specifically, if you do have a patient that is on one of those that you are not going to move, going down from 150 milligrams twice a day to 100 milligrams twice a day.

You can pre-emptively do that because of the serum concentrations being increased at a pretty controllable level. However, in the space of inducers, whether you are discussing the ribociclib or the abemaciclib, you really do not have any leeway as far as that is concerned. It is going to increase the concentration to a point where we do not know how far we would have to decrease the dose for it to be safe.

Select Drug–Drug Interactions That May Affect CDK4/6i Use

Then I will get into more medications because with ribociclib, making sure that you are being mindful of what other medications are on the patient's medication history that could possibly prolong the QTc interval, whether it be antipsychotics, antiarrhythmics, some antibiotics and those acute situations and if they have antidepressants that can possibly interact with ribociclib to exacerbate that QTc prolongation.

CYP3A4 inhibitors, as I mentioned before, the clarithromycin/erythromycin. They have verapamil, which of course not used as much in the cardiology space as it was at one point. Then the CYP3A4 inducers with the steroids, specifically carbamazepine and phenytoin.

Looking at your roadmap, when you talk about hematologic toxicity in the early-stage breast cancer setting with the CDK4/6 inhibitors, holding and letting the patient recover naturally is essentially the strategy here.

Resuming at the lower dose depending on what grade of neutropenia showed, typically grade 3. Understanding that when you do resume to bring it down to dosing level, especially if it is persistent, omitting the G-CSF when that may be indicated in this patient population. Also understanding that while we are treating early-stage breast cancer patients, they have the ability to become metastatic. If you are noticing that you are looking more at pancytopenic patients as opposed to just limited to neutropenia, it could be metastatic disease.

Then antibacterial prophylaxis not being indicated in the early stage of setting.

I am starting off with diarrhea with abemaciclib. Grade 2 diarrhea, which is something that I will interject in each of these toxicities, talking about what is my strategy with my particular patients. Understanding that if they have grade 2, as long as the anti-diarrheal and the supportive care causes the grade 2 diarrhea to subside, you can actually restart at the same dose. If it is persistent and the patient does continue to have grade 2 with the dose being held, that you will need to reduce the dose when you do restart.

Low fiber diet, low fat diet, smaller frequent meals, adequate hydration, all great things to tell patients in reference to diarrhea associated with abemaciclib.

Monitoring and Managing Abemaciclib-Induced Hepatotoxicity

Hepatotoxicity. Just speaking to this understanding that you are going to test the patient's labs every two weeks for the first two cycles and then monthly for two cycles. I typically go ahead and go out another two to four months, understanding that the hepatotoxicity typically would show up a bit later in therapy. Not necessarily going to be something you are going to see early on, but definitely month four, month three, you can possibly start to see it a little bit more frequently. So making sure you are on top of those labs.

Monitoring and Managing Ribociclib-Induced Hepatotoxicity in Early-Stage Breast Cancer

Talking about the ribociclib hepatotoxicity. Same conversation about the every two weeks, checking the labs on the first two cycles and then continuing on with your judgement clinically thereafter, but understanding it can show up at a later time and that the fact that the ribociclib is being dosed at 400 milligrams daily three weeks on, one week off, versus the 600 milligrams that you see in the metastatic setting. You have one opportunity to reduce the dose before you need to discontinue therapy.

Monitoring and Managing CDK4/6i-Induced Neutropenia

Neutropenia, I spoke to this. If you have a patient who has that grade 3 neutropenia, is there an infection? Is there a fever that is associated with it? If so, of course, reducing the dose till they go to grade 2, and then holding the dose and then reducing the dose once they get to grade 2.

If they are a patient who has just had grade 3 neutropenia with no fever and no infection, then you could actually resume the dose after they go to grade 2 and then start at the reduced dose.

Thrombotic Events in Patients on CDK4/6 Inhibitors: Summary

Thromboembolic events. The key to talk about here is that these patients, if they do develop a clot while on the CDK4/6 inhibitor, making sure you get them anticoagulated adequately after you hold the dose and then resume it once they are anticoagulated. It can be at the same dosing level when you do restart the dose.

Monitoring, Managing and Mitigating VTE With Abemaciclib

Monitoring for VTE. Suspending the treatment, when you are talking about abemaciclib and making sure the patient understand the signs and symptoms of DVT as well as PE is something to make sure you have in your education portfolio when you are talking to patients as they start the therapy.

Monitoring QT Prolongation With Ribociclib

Then rounding off some of our conversation about QTc prolongation with ribociclib. Making sure you are monitoring electrolytes and EKGs and making sure that you have that every two-week EKG that you are going to start when they initiate therapy. Avoiding those antipsychotics, avoiding some of those medications that might actually exacerbate the QT prolongation.

QTc Prolongation With Ribociclib and Dose Modifications

Then understanding that there is a threshold, whether it is 480 milliseconds or it is 500 milliseconds, if the patient is rising above that 500 milliseconds, you start to get into the space where you are going to have to discontinue pretty early on.

If you can get them at the 480 and reduce the dose and they stay below that, you would be able to continue on just with the lower dose of the 200 milligrams. Once again, after the 200 milligrams is not tolerated, you will have to go ahead and discontinue therapy.

Renal Toxicity With Abemaciclib: Mechanism of Action

Definitely want to speak to this. With abemaciclib, patients will typically have a 0.2 to 0.3 milligram per deciliter increase in serum creatinine that you will see. This is just the explanation behind the transporters in the proximal tubules that caused that creatinine to be decreased as far as being excreted in the urine and you get those elevations reversible when the therapy stops. But something I know patients frequently will come up to me and ask me why they were at 0.9 pretty consistently prior to starting this in the adjuvant setting, and now they are swimming around at 1.2, 1.3, pretty consistently. I will have this conversation with patients pretty frequently.

Roadmap for Managing ILD With CDK4/6 Inhibitors

Just a roadmap to ILD. This is in the adjuvant setting. So understanding that you do have patients that would not get as many of those scans of the chest as you would see in a metastatic setting. You really have to be mindful of the patient's understanding the symptoms, understanding that there could be infections, but also making sure you are scanning them if they are showing signs of symptoms of ILD.

Key AEs With Adjuvant CDK4/6 Inhibitors: Monitoring and Prevention

As I round off some of the toxicity here. With the abemaciclib and ribociclib, you will see the diarrhea, but more pronounced with the abemaciclib. The hepatobiliary toxicity, you can see that in both spaces. The neutropenia, you can see that in both spaces, while the abemaciclib may be a little bit less pronounced than ribociclib.

The VTE something that is reported specifically with abemaciclib. The ILD something that you would see with ribociclib and the abemaciclib. So just monitoring for those pulmonary symptoms I was referring to. The QTc prolongation being something that is an exclusive to ribociclib at this point.

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

Fatigue, which is actually the third most common reason that the patients would discontinue therapy when you looked at the registry trials. It is something that is not talked about as much, but the exercise being something that can address the fatigue and help patients. The elevated serum creatinine, as I talked about those proximal tubule interactions with the transporters being something that you see specifically with abemaciclib. Then you do have some skin adverse effects that you can see with abemaciclib and ribociclib.

Myth 2: Switching CDK4/6 Inhibitors Is a Preferred Strategy for Toxicity Management

Going to the strategies and the toxicity management as we round off everything. A guideline-directed dose interruption is something that we discussed and you can definitely employ. As a pharmacist, get that question very frequently from the oncologists about what is the thing to do in these different clinical situations in the clinic?

Switching agents, maybe not as much the true direction we want to go. Addressing the patient's dose and seeing if that can get them consistently through the entire regimen would be more of the space that I would air in. Then looking at pharmacist-led strategies to optimize therapy, whether it be the follow-up with patients after several days and looking at what their diet looks like, what are they doing as far as the antidiarrheals, the timing of dose interruption, like making sure you have a stepwise way of reducing the dose.

The medication reconciliation, making sure drug-drug interactions are also being avoided.

Posttest 3

We will go back to J.C. That was the 56-year-old patient, postmenopausal women with HR+/HER2- early stage breast cancer that had been started on abemaciclib with letrozole. Had the ANC that was 950. I will open it up to the audience again as we talk about this patient.

1. We reassure the patient about the diarrhea improving and encouraged PRN antidiarrheals;
2. We talk to the patient about a plan to follow-up within 72 hours with the diet guidance and looking at escalation criteria;
3. Recommend prophylactic antidiarrheals; or
4. Pre-emptively hold the abemaciclib to the next visit to prevent worsening symptoms.

Okay. Yes, definitely in the audience, we did get an increase in the correct answer, which is counsel patients and plan follow-up within 72 hours with diet guidance and escalation criteria. Some still held tight with the reassurance of the diarrhea improving and encouraging PRN antidiarrheals.

The daily prophylactic antidiarrheals for the rest of the therapy has been proven that daily prophylactic antidiarrheals actually causes constipation across the board. They did try this in some of the trials to try to see if they could pre-emptively treat the diarrhea and constipation went up substantially, so not necessarily the option there.

Then pre-emptively holding the abemaciclib at the next visit to prevent worsening symptoms, also something that we probably would not take that direction either.

Myth 3: Dose Reductions Compromise Efficacy in Early Breast Cancer

Okay. I am going to start with our third and final myth, which is dose reductions and compromising efficacy in early breast cancer.

Poll 4

For the fourth question, how consistently do you use pharmacist-led communication strategies to support toxicity management, adherence, patients receiving adjuvant CDK4/6 inhibitor in high-risk HR+/HER2- early stage breast cancer?

Case Study 4

Okay, we will go to our fourth case, which is A.C., who is a 58-year-old woman receiving adjuvant ribociclib with endocrine therapy who presents at month four with grade 3 neutropenia, 800 cells, but is otherwise asymptomatic. She is highly motivated to continue therapy but is concerned about the dose changes affecting efficacy.

Pretest 4

What is the most appropriate pharmacist-led intervention?

1. Continue current dose and repeat labs in four weeks;
2. Hold ribociclib until recovery to grade 2, then resume at the same dose;
3. Hold ribociclib until recovery to grade 2, then resume at the same dose; or
4. Switch to abemaciclib to avoid further neutropenia.

Okay. Where I thought we would be as far as either holding the ribociclib until grade 2 and then resuming the same dose or the reduced dose. It is always a conversation. The patient being asymptomatic and not having fever, something we will discuss.

Dose Reduction Studies of CDK4/6 Inhibitors

Dose reductions. This is in both of the registry trials in the adjuvant setting of early-stage breast cancer with abemaciclib and ribociclib, with the monarchE showing a follow-up of 6.3 years. Then still, even with those dose reductions and those doses being held having same invasive disease-free survival when you look at the groups.

Same thing with ribociclib. They had follow-up at the five-year point. Invasive disease-free survival also stayed consistent with early and frequent discontinuations. This was captured in a real-world trial. Both of which showing consistent efficacy with the dose reductions and the doses being held.

monarchE Dose Reductions and Discontinuations

As we look further into the monarchE as far as dose reductions are concerned and discontinuations, you see that in that trial, 44%. So pretty substantial amount of dose reductions occurring. Also when you look at discontinuation altogether at 18.5%. The key is just looking at efficacy and the consistency of efficacy and how it did not reduce the invasive disease-free survival in monarchE with these numbers as far as dose reductions and dose continuations.

Just to add to that, even the discontinuation after you had a dose reduction was at 9%. You had some patients that they did attempt to reduce the dose, and they still had to end up discontinuing but still able to maintain the invasive disease-free survival endpoint.

I will pass it over to Julia now to finish up with NATALEE as we go into the questions.

NATALEE Dose Reductions and Discontinuations

Julia Ziegengeist: Yes. Similarly with the NATALEE trial, we see that over 25% of patients in NATALEE required a dosing reduction, and discontinuations ended up being about 20% as well.

We still see that patients, even if they did require a dosing reduction, still had a durable iDFS benefit at that five-year time point.

Early Adjustment Matters More Than Dose Intensity

We know patients are going to have toxicities. We cannot always prevent that even though we try to use good supportive care to manage them. We try to get ahead of them, aggressively manage them and pre-emptively tell the patients what to expect, it is still going to happen.

Dosing reductions tend to occur early because of those trial protocols. We want to ensure that if a patient does require dosing reduction, because we have managed it as best we can with supportive care, that we still go ahead and do that because we know that dosing reductions allow us to continue the treatment and lead to higher treatment persistence.

Dose Optimization Is a Marker of Good Care

You may have providers, or oftentimes in my practice, I see it is really the patients that are hesitant to reduce the dose. We have done a lot of things to try to supportively manage whatever toxicity they are having, and we get to a point where dosing reduction is needed.

We can encourage them that we are reducing the dose so that we can actively manage that toxicity. We are maintaining and hoping to maintain better quality of life. It is a strategy for us to maintain that long-term therapy, because we know that getting two or three years in of these agents is benefiting them, not only for that time that they are taking it, but now we know five to seven years, we are still seeing a benefit. So trying to keep them on the therapy is most important rather than maintaining any dose intensity and having them suffer with whatever side effect it is. It also allows us to support adherence.

Dosing reductions are proven that in this case they do not lose efficacy. They are not a treatment failure and they are not necessarily a reason to immediately switch agents.

Myth 3: Dose Reductions Compromise Efficacy in Early Breast Cancer

We have dispelled myth number three at this point. We see that evidence supports similar efficacy for both adjuvant CDK4/6 inhibitors regardless of whether patients were dose reduced or not. We want to maintain this treatment duration for the two to three years and maximize that quality of life while we are ensuring that the patient is also safe.

On the flip side of this, I also commonly get the question from patients. Well, if you are okay with dose reducing, then why would you not just start me at the lowest dose and then we can creep up if you feel like it is necessary? To that I respond, well, we want to try and pursue the FDA-approved dose. Patients who were dose reduced in the trial were doing so because they were having a toxicity. That does not necessarily mean that we should always be starting patients at the lowest dose.

However, that could be a strategy in shared decision-making with the patient to say, “Let us try it at that lowest and see if we can increase it.” There is some studies going on in the metastatic setting looking at starting patients at the lowest dose and then increasing them. As long as that is a conversation with the patient, that is a strategy that you could potentially utilize, but knowing that patients really received a dosing reduction because they needed it in the trial.

Posttest 4

Post-test. We will look at this case study with A.C., who was a 58-year-old woman who had ribociclib with the grade 3 neutropenia. She is motivated to continue. What are we going to do? What is the most appropriate pharmacist-led intervention in this setting?

With this one, I would actually say let us follow the prescribing information and hold ribociclib until they recover and resume at the same dose. At the slightest hint of a toxicity does not necessarily mean that we need to immediately reduce the dose. However, prescribing information would say if they have a recurrent neutropenia, that is when we can go ahead and do that. We can encourage the patient that we are not necessarily decreasing their chance for a benefit with iDFS. Of course, let us see how it goes with the second cycle.

Resources for Optimizing the Use of CDK4/6 Inhibitors in HR+/HER2- Breast Cancer

There is a couple of resources that you might find useful, and if you download the slide set, you will actually get the hyperlinks within it to access these. So interactive tool for managing AEs with these CDK4/6 inhibitors. Then also a patient resource that you might find helpful.

Poll 5

Do you plan to make any changes with your clinical practice based on what you learned in today's program?

Poll 6

Okay. Please take a moment to enter. One key change you plan to make in your clinical practice based on this education?

Q&A

Thank you all so much for coming. We will take questions at this point. Feel free to enter anything within the iPads. We might have had some already come in.

Rodney Hunter: I can read the first one, which is, how do you see pharmacist's role evolving as CDK4/6 inhibitors move into the earlier lines of therapy or different disease settings?

I will chime in on this one and just saying that as we start using it more and more in patients in the early stage, the follow-up in the key adherence and us staying heavily involved in adherence would be really the place where pharmacists can really make our mark.

Julia Ziegengeist: Definitely. Through a lot of the things that we mentioned in this presentation and then also those key counselling points for them as well.

Got an interesting one coming from an audience member as well. What recommendations do you have in navigating interactions between long-term antipsychotic use? The example given was quetiapine with a category X drug-drug interactions and initiating ribociclib for high-risk node-negative patients.

This comes up frequently. I do not know how much you see it too, Rodney. I am sure you do with a lot of long-term drugs that patients are taking. It really depends on what exactly is that interaction. If it is QTc prolongation, it is very patient specific. What is their baseline QTc? Let us monitor a little bit more frequently.

If it is something more like a CYP3A4 interaction, that is a discussion with whatever provider is prescribing that long-term medication to see what have they tried before? Or is there anything that we could potentially switch them to, to allow us to use this medication. That would be equally effective for whatever disease state they are managing. Do you take any different approaches?

Rodney Hunter: No, pretty consistent there. When you have an immovable object, you have to get creative at times, especially if they are stable on the drug that is interacting.

Julia Ziegengeist: For sure.

Rodney Hunter: Let us see what else do we have here? How do pharmacists optimally educate patients on early identification and management of adverse effects without increasing unnecessary treatment interruptions?

This is probably one of the more important ones. A very good educational tool, whatever companions you all use. We, as pharmacists, sometimes make our own companions. Sometimes the companies have things they have made. The better informed the patient is up front of the toxicities, the better they are managed.

When they surprise the patient at home and they have heard nothing about the toxicity, that is when I feel like there is not only sometimes trust that is lost about the patient in you as far as your communication is concerned, but also it deters them from wanting to continue the medication because they are like, what other things am I not knowing about the treatment I am starting and I have been taking for a period of time. So pre-emptively going in and making sure they understand all of the toxicities, even if it is daunting, is a good strategy.

Julia Ziegengeist: For sure. We had several good ones come in. What are your thoughts on VTE prophylaxis for patients on verzenio and tamoxifen?

In our setting, usually, we are not using any form of VTE prophylaxis for our patients, not necessarily required for this combination. Obviously, we know that tamoxifen comes with its own risk of VTEs as well as verzenio. We certainly have had patients who have developed a VTE on these drugs. For that, I would say I am usually not prescribing any prophylaxis upfront. We know that obviously bleeding risk and things like that are patients often may get reconstructive surgeries as well, which would require holds.

Overall, potentially bleeding risk probably outweighs the benefit in this setting. Certainly, counselling them to be on the lookout for any of those types of signs and symptoms of a VTE.

Rodney Hunter: This one is about infections. It is asking, do you hold therapy during active infections when not neutropenic? If so, what duration?

My short answer to that is yes. If they actually have an active infection, even if they are not neutropenic, we will actually hold a therapy. Usually, I do actually resume typically after they finish the antibiotic course. So immediately after they finish the antibiotic course, I usually will instruct the patient to start again, especially drug interactions. I am usually trying to do the best that I can to avoid any other toxicity outside of the infection.

When I saw that question too, something came to mind in related to also surgeries, even if it is not something related to breast surgery. They are having a knee replacement or something like that. Even if they have not demonstrated neutropenia or thrombocytopenia, we usually hold during those times as well. That is not something that a patient may always think to ask.

Oftentimes, it is unclear, especially if they are going to a different health system that their surgeon even knows they are on these agents. So important for a patient to know that so that they can let us know when they have things like that going on too.

Rodney Hunter: Sure. This is a good one. What role do pharmacists play in overcoming access issues such as prior authorizations, dose delays, or financial toxicity?

I can just speak for our model that the cancer center that I practice at is that we own 100% of these three aspects of the patient's treatment. Once the medication is initiated, we work with a specialty pharmacy to help with those prior authorizations to get the patient access. Once the patient does have a dose delay, we sometimes are facilitating the new dose being given as far as the dose reduction, we will actually follow up with the patient to tell them when to restart the medication and make sure there is good communication now or maybe they need to go down to grade 2, maybe we need to get labs to see that they have improved to grade 2 from grade 3 on a toxicity.

Then finally with the financial toxicity, PAP programs to help patients who are either underfunded or uninsured. Also, patients who naturally just have extremely high copays that are on Medicare. We are involved in all of those processes.

Julia Ziegengeist: Yes. If you are lucky enough to have support from an internal specialty pharmacy or technicians, things like that, that can be a really fantastic resource to try and help get patients access to these medications, because it can definitely be challenging.

Rodney Hunter: Definitely.

Julia Ziegengeist: Insurance companies are taking on more understanding that these drugs are being recommended initially. That was a little bit of pushback to get approval for them, but it has been better now.

Last one we will do. How do you manage timing of labs to ensure they are done at appropriate intervals? For example, a patient has an office visit scheduled on day four instead of day one.

That is definitely some education to the team, particularly, like nursing staffs usually involved in helping to make sure all of those things get scheduled. We, as pharmacists, can play a role too. I am frequently contacting patients to say, “Okay, what day did you actually start your medication?” That way we can make sure that those appointments are aligned.

If we need to have them come on a different day to get labs, it is not ideal, but emphasizing that we need to make sure that what we are getting is accurate as well. So we can play a role and then also educating the team.