So let's start with a little background information. Breast cancer is the most common malignancy among women in the United States and remains the second leading cause of cancer death after lung cancer.

Historically, HR+/HER2- breast cancer had a median time to progression of about 1 year on endocrine therapy or chemo alone. And in the metastatic setting, the overall survival of only about 2.5-3 years. Since the first FDA approval of palbociclib in 2015, the CDK4/6 inhibitors have doubled progression-free survival from about 1 year with endocrine therapy alone to 2‑3 years. And real-world data shows that overall survival now often exceeds 4-5 years. These agents, palbociclib, ribociclib, and abemaciclib, have transformed breast cancer management. A CDK4/6 inhibitor combined with endocrine therapy is the first-line standard-of-care treatment in the metastatic setting.

Additionally, today we'll talk about early breast cancer, where abemaciclib and ribociclib are approved for patients who are at high risk for recurrence.

[00:02:20]

MBC: Choosing the Optimal CDK4/6 Inhibitor

So in the metastatic setting, all 3 of the CDK4/6 inhibitors plus endocrine therapy combinations are strongly recommended, category 2A or higher per NCCN. All 3 agents improve progression-free survival, but only ribociclib has shown a statistically significant overall survival benefit.

This resulted in its category 1 preferred recommendation from the NCCN when combined with an aromatase inhibitor for metastatic disease. For patients with endocrine resistance, both ribociclib and abemaciclib in combination with fulvestrant have a category 1 recommendation.

[00:02:56]

Choosing the Optimal BC Therapy

So when selecting the optimal breast cancer therapy, it's important to consider individual patient factors such as cardiac or liver disease that may influence drug choice.

In the early breast cancer setting, eligibility also depends on the stage and certain high-risk criteria. For both, we need to evaluate the choice of endocrine therapy, whether it be tamoxifen or an aromatase inhibitor. And in high-risk premenopausal women, ovarian function suppression should be considered. So there are many factors to weigh, making an open discussion with patients essential.

Now I'm going to turn this over to Amy for a case discussion and polling question.

Amy Goodrich: Thank you. So let's jump into a case study.

[00:03:42]

Patient Case 1

So, Sally is a 58-year-old Black female with stage III right breast cancer. She underwent right mastectomy. She received adjuvant docetaxel and cyclophosphamide for 6 cycles and adjuvant radiation.

She presents today to discuss adjuvant endocrine therapy with a CDK4/6 inhibitor.

Past medical history: She's got hypertension. She is on hydrochlorothiazide and verapamil, which we all know is a strong CYP3A inhibitor. Baseline CBC is notable for a neutrophil count of 1.3. Her other chemistries and her EKG are all normal.

[00:04:30]

Poll 3: Based on past medical history, concomitant medications, and mild neutropenia, which adjuvant CDK4/6 inhibitor in combination with endocrine therapy would you consider the most appropriate for Sally?

So based on this past medical history, concomitant medications, and mild neutropenia, which adjuvant CDK4/6 inhibitor in combination with endocrine therapy would you consider most appropriate for Sally?

1. Abemaciclib;
2. Ribociclib;
3. Either of those, or
4. Endocrine therapy alone.

Which do you think is the best answer? And I'm going to give you a few seconds to come in and answer that question.

Okay. So let's hear what the right answer is in our content here.

Elizabeth Diaz: I missed the – sorry about that. I missed what the poll said, but I think the correct answer would be abemaciclib, and that's because ribociclib causes more neutropenia, but we're going to get into that more in the next section on the side effects.

[00:05:48]

Review of Combination CDK4/6i + ET in High-Risk EBC

So let's discuss their use in early breast cancer for adjuvant therapy in high-risk patients.

The purpose here is to prevent them from developing or at least delay the onset of metastatic disease. The monarchE trial showed that 2 years of abemaciclib with endocrine therapy showed a 30% reduction in recurrence risk and an absolute benefit of 3%-4% at 2 years. More recently, the NATALEE trial has demonstrated that 3 years of ribociclib plus an aromatase inhibitor also provides benefit across a broader risk population. NATALEE showed a 25% reduction in recurrence risk with an absolute benefit of 3% at 3 years. But now we don't have overall survival data yet for these trials.

[00:06:40]

What Is "High Risk" in HR+/HER2- EBC?

So what is high risk? Well, it's defined by clinical factors, including large tumor size, nodal involvement, and high grade, all of which raise recurrence risk.

Tumors with a high KI-67 score greater than 20% tend to grow faster and carry a worse prognosis. Tumors with low estrogen or progesterone expression also increase in recurrence risk because they do not respond as well to endocrine therapy. On a molecular level, genomic alterations converge to affect apoptosis, cell proliferation, and immunogenicity, contributing to aggressive biology.

This genomic risk is determined by additional genetic testing of the tumor, usually at the time of diagnosis. For example, in my practice, we use Oncotype. There’re several other commercially available tests.

[00:07:38]

Risk Assessment Criteria for Adjuvant CDK4/6i Therapy

So in these 2 clinical trials, the criteria they used to select high-risk patients differed. In monarchE, patients needed to have 4 or more positive axillary nodes or at least 1 positive lymph node with an additional high-risk factor. These factors include tumor size greater than 5 cm, grade 3, or a high proliferation index.

But in the NATALEE trial, patients only needed to have at least 1 node, nothing else. And then they even included some patients with node-negative disease, but they had to have 1 of those high-risk factors. So the NATALEE trial used broader inclusion criteria, making more patients eligible, really kind of in the stage – early-stage of breast cancer, mostly stage IIA, eligible for adjuvant treatment with ribociclib.

[00:08:24]

monarchE and NATALEE Trial Populations

And so this chart is kind of a good reference to save and refer back to because it can be a little confusing. Maybe it's best to give you an example. So if you think of a patient that's stage IIA, maybe with a tumor 3 cm, so it would be T2, and node-negative.

So, N0, you can see that line there where there's yellow and then red under the abemaciclib. So since she's node-negative, she's not eligible for abemaciclib under the monarchE eligibility criteria. In addition, she's grade 2 and had an Oncotype score of 31.

So, she received adjuvant chemotherapy. And so then looking at that yellow box, since she does have grade 2 and a high genomic risk with that Oncotype score over 26, then she would be eligible to get ribociclib for 3 years in the adjuvant setting.

[00:09:20]

Approvals and Recommendations: Adjuvant Abemaciclib + ET

This is just kind of a summary where abemaciclib is approved, category 1 preferred by NCCN, and really has the same recommendations from ASCO.

[00:09:32]

Approvals and Recommendations: Adjuvant Ribociclib + ET

Now for ribociclib, things are a little different. The ASCO made their recommendation conditional, with abemaciclib actually favored if the criteria overlap. And the reason they favor abemaciclib is due to longer follow-up, deeper benefit, and the shorter duration of 2 years.

So right now, these are the current recommendations until the overall survival data is mature.

And before we dive into the side effects of these therapies, I'll hand it back to Amy to revisit our patient case.

[00:10:09]

Patient Case 1 (cont'd)

Amy Goodrich: Sure. So, Sally started adjuvant abemaciclib 2 months ago. She calls to report 7-8 episodes of diarrhea despite taking as-needed antidiarrheals. And there's no predictable pattern to her diarrhea. She says her weight is stable. She's eating and drinking well. She's fatigued. She is sleeping well. She's having trouble working because of her fatigue.

You ask her to stop taking abemaciclib until her symptoms are resolving.

[00:10:44]

Pretest 1: Once her diarrhea has resolved, what additional counseling would you provide for Sally as the most appropriate next step in her treatment?

So pretest number one: Once her diarrhea has resolved, what additional counseling would you provide to Sally as the appropriate next step in her treatment?

1. She should start abemaciclib with no change in the dose or the schedule and increase her antidiarrheal regimen;
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 therapy and continue on endocrine monotherapy.

And so I'm going to give you a minute to read all these through.

Okay. So the – C is the number 1 answer so far. 43% of you said C. So let's see if that's right.

An APP-Driven Approach to Monitoring and Management of AEs to CDK4/6 Inhibitor Therapy

[00:11:48]

Julia LaBarbera (UCLA Hematology Oncology): Great. Thank you, Amy. And hello, everyone. Thank you for having me today. We'll be going into more detail about side effect monitoring and management for the 3 CDK4/6 inhibitors for breast cancer.

[00:12:04]

Comparing Serious/High-Risk Toxicity Profiles of CDK4/6 Inhibitors

So when we're selecting a CDK4/6 inhibitor for our patient, it's important to note the black box warnings associated with each agent.

Abemaciclib can cause severe diarrhea, neutropenia, hepatotoxicity, as well as a small but significant risk for interstitial lung disease or pneumonitis and VTE. Palbociclib has a black box warning also for neutropenia and interstitial lung disease. And ribociclib can cause QT prolongations, severe skin reactions, as well as significant hepatotoxicity, neutropenia, and also ILD.

[00:12:48]

Notable AEs With CDK4/6 Inhibitors

There are additional side effects to consider for each agent. All are associated with some degree of nausea. So you will want to counsel your patients on appropriate nausea management, you know, whether that's anti-emetics or taking each drug with food or a light snack as needed.

While diarrhea is most common with abemaciclib, it still may occur with ribo and palbo, but usually to a lesser degree. And we'll touch on management a little bit later on.

In addition to neutropenia, anemia and thrombocytopenia can occur with all 3 of these drugs. So it's just something to watch out for and counsel your patients on. Hair thinning and fatigue can also occur with each agent.

[00:13:38]

Key Differences With Abemaciclib, Palbociclib, and Ribociclib

So what are the key differences and side effects between the 3 CDKs that would affect which agent I'm likely to select for my patient?

Well, the diarrhea with abemaciclib can be severe, but it's typically manageable. And we'll get into that in just a minute. Ribociclib can cause hepatotoxicity that may recur despite dose reduction. QT prolongation may also occur and typically is seen around treatment onset. With palbo and ribo, neutropenia may be more pronounced than with abemaciclib. However, for all 3 agents, growth factor support is rarely needed.

[00:14:23]

Monitoring and Managing Abemaciclib-Induced Diarrhea

So thinking back to our patient case, what are the recommendations for monitoring and management of abemaciclib-induced diarrhea? We want to teach our patients to initiate antidiarrheals and increase oral hydration at the onset of loose stools. Further management then depends on severity.

For grade 1 or less than 4 stools per day above the patient's baseline, we can continue abemaciclib at the same dose with supportive management. For grade 2 or between 4-6 stools above baseline that persists beyond 1 day, we advise patients to hold therapy until diarrhea resolves to at least a grade 1 and then resume at the same dose. If grade 2 diarrhea persists beyond 1 day or recurs despite maximizing supportive care and treatment hold, then a dose reduction is indicated.

Now for grade 3 diarrhea, which is 7 or more stools above our baseline, which is what our patient's been experiencing, we want to hold treatment until symptoms resolve to at least a grade 1 and then reduce the dose of abemaciclib. And we've included the guidelines for dose reduction here at the bottom for your reference.

[00:15:42]

Practical Management Strategies: Diarrhea With Abemaciclib

These are some teaching points to convey to your patients when initiating abema and discussing diarrhea.

This does seem to be more common in the first couple of months after starting therapy and often improves over time. Teach patients to recognize signs and symptoms of diarrhea and have a plan in place for management, which includes having Imodium on hand and reviewing strategies for hydration and when to call the office with any concerns or red flag symptoms.

Let's Revisit Our Case

[00:16:16]

So let's revisit our case.

Back to you, Amy.

[00:16:23]

Patient Case 1

Amy Goodrich: Sure. So Sally started adjuvant abemaciclib 2 months ago. She's having diarrhea, her weight's stable. She's using antidiarrheals. She's not able to work. She's also fatigued.

So you ask her to stop the abemaciclib until her symptoms are resolving.

[00:16:42]

Posttest 1: Once her diarrhea has resolved, what additional counseling would you provide for this patient as the most appropriate next step in her treatment?

And so once her diarrhea has resolved, what additional counseling would you provide as the most appropriate next step in her treatment?

1. She should restart the abemaciclib with no change to the dose or schedule and increase her antidiarrheals;
2. She should restart the abemaciclib with a dose reduction and continue antidiarrheals as needed;
3. She should switch from abemaciclib to ribociclib due to the toxicity, or
4. She should stop the CDK4/6 inhibitor and just continue with endocrine monotherapy?

Okay. So we've got a number of responses already, and B is the winning answer at this point with 69%.

[00:17:41]

And so do you want to talk about the rationale here?

Julia LaBarbera: Yeah. Yeah. So, as mentioned, this patient is experiencing grade 3 diarrhea. So a dose reduction from abemaciclib is indicated as well as maxing out her antidiarrheal medications as needed. If a dose reduction strategy does not work, you can consider switching to ribociclib at that point. But I would not abandon abemaciclib right off the bat without trying some additional strategies and dose reduction before considering a change in therapy.

Amy Goodrich: Great. Thank you.

Julia LaBarbera: Thank you.

[00:18:32]

Monitoring and Managing CDK4/6i-Induced Neutropenia

So now we'll just dive into some of the most common side effects that you're likely to encounter with CDK4/6 inhibitors, starting with neutropenia.

The recommendations for monitoring and managing neutropenia are included in this flowchart here. We will want to collect a CBC with a differential at baseline, and the start of each cycle, with additional recommendations for CBC check in cycle 1 and 2, depending on the drug that you're giving.

For grades 1 and 2 neutropenia, which is an ANC greater than or equal to 1,000 up to the low limit of normal, no dose modification is required for neutropenia, and we can continue therapy as long as the patient is doing well. We may consider holding treatment for illness or infection at this level, just depends on how your patient's doing.

For grade 3 neutropenia, which is an ANC between 500-1,000, we first want to evaluate for any fever or any other signs of infection. If no fever or infection, it's recommended to hold the treatment until neutropenia resolves to at least a grade 2 and then resume at the same dose. If the patient has grade 3 neutropenia with a fever or infection or has a recurrent grade 2 neutropenia, we want to hold treatment again until the ANC improves and resume with the dose reduction.

It's important to note that unlike chemotherapy, neutropenia with CDK4/6 inhibitors is reversible by holding treatment. As the white blood cells are just in senescence or asleep from the CDK4/6 inhibitor, not destroyed like they are with chemotherapy. So these white cells “wake up" when the treatment is held, allowing the body's natural immune function to take over at that point. So I always advise my patients to keep me apprised of if they're unwell or have any virus or other illness, and we consider holding the treatment until the patient is doing better.

[00:20:54]

Comparative Monitoring and Dose Adjustments for Neutropenia Associated With CDK4/6i

Here we've included the schedule of CBC monitoring recommendations for each agent for your reference, as well as dose reduction guidelines when needed.

[00:21:11]

Monitoring and Managing Abemaciclib-Induced Hepatotoxicity

All right, for hepatotoxicity, the management strategies differ somewhat depending on whether we're using abemaciclib or ribociclib.

For abema, we want to collect LFTs at baseline every 2 weeks for the first 2 cycles. Then monthly for cycle 3 and cycle 4, and then as clinically indicated. We can continue treatment through grade 1 and 2 LFT elevations, as long as the bilirubin is below 2 times the upper limit of normal. We want to hold abemaciclib for grade 3 LFT increases, which is 5-20 times the upper limit of normal, or with persistent or recurrent grade 2 elevations, and monitor for improvement to at least baseline or grade 1.

As long as the bilirubin has remained within 2 times the upper limit of normal, you can resume treatment at the next lower dose. For any grade 4 hepatotoxicity or any AST/ALT increase with concurrent hyperbilirubinemia more than 2 times the upper limit of normal, we should permanently discontinue abemaciclib. And again, the instructions for dose reduction guidelines are included here.

[00:22:30]

Expert Recommendations on Monitoring and Managing Ribociclib-Induced Hepatotoxicity in Early-Stage BC

So for ribociclib, we differ slightly in management of hepatotoxicity in the early breast vs metastatic setting. The initial lab monitoring is the same as with abemaciclib. However, it's recommended to hold therapy with a grade 2 LFT elevation or higher, again, as long as the bilirubin is below 2 times the upper limit of normal.

We want to wait to resume treatment until the LFTs have returned to at least the patient's baseline, then restart ribo at the next lower dose. If grade 2 or higher hepatotoxicity recurs despite this dose reduction, then we should permanently discontinue ribociclib.

We tend to manage hepatotoxicity more conservatively in the early breast setting than in metastatic disease because in the early breast setting, we're starting patients off at a lower dose of 400 mg daily compared to 600 mg daily for metastatic disease. So, LFT increases at lower doses are more concerning.

It's also important to note that hepatotoxicity with ribociclib does not appear to be dose dependent, and this AE may recur with rechallenges despite these dose reductions.

[00:23:50]

Monitoring and Managing Ribociclib-Induced Hepatotoxicity in Advanced BC

Now in the advanced or metastatic setting, we can consider rechallenging ribo at the same dose level with the first onset of grade 2 LFT elevation after initial treatment hold and then move to the next lower dose if grade 2 toxicity recurs.

With the first occurrence of grade 3 LFT elevations, we will want to hold treatment until this improves and then resume at the next lower dose. But for persistent grade 3 elevations, a grade 4 LFT bump, or any instance of elevated enzymes and a T-bili greater than 2 times the upper limit of normal, we should permanently discontinue therapy.

[00:24:34]

Monitoring, Managing and Mitigating VTE With Abemaciclib

For QT prolongation with ribociclib, check baseline EKG and electrolytes prior to starting therapy. Repeat the EKG at cycle 1, Day 14, and then as clinically indicated. Follow electrolytes at the start of each cycle for at least 6 cycles and then as indicated. Try to avoid concomitant drugs known to prolong the QT interval, including and especially tamoxifen, as well as strong CYP3A inhibitors.

Teach patient signs and symptoms to report and when to contact your office with concerns. And interrupt treatment for any QTcF prolongation more than 480 ms. And lastly, appropriate patient selection is imperative.

I would not recommend ribociclib for any person with a history of long QT syndrome, uncontrolled or significant cardiac disease, or any underlying electrolyte abnormality.

[00:25:38]

Monitoring QT Prolongation With Ribociclib

Oh, I'm sorry. This was a slide for monitoring QT prolongation with ribociclib that I just went through. I've totally skipped the VTE one. So let me just go back to that.

[00:25:54]

Monitoring, Managing and Mitigating VTE With Abemaciclib

All right. You've already seen this one but remember that VTE is a black box warning for abemaciclib. And while the risk is low, usually around 2%, we want to make sure we're educating patients about the possibility of this toxicity, as well as any red flag symptoms, including unilateral extremity pain or swelling, new shortness of breath, chest pain, increased heart rate, or increased respirations.

You will want to treat DVT or PE as medically appropriate. Hold treatment until the patient is clinically stable, then discuss risk benefits or resuming therapy for your patient.

[00:26:34]

Managing Abemaciclib- and Ribociclib-Induced ILD

Okay. All right. So for interstitial lung disease, all 3 of the CDK4/6 inhibitors carry this risk. You want to look out for any new cough or shortness of breath, hypoxia, or interstitial infiltrates on chest imaging.

For grade 1 or asymptomatic ILD with ribo or abemaciclib, initiate appropriate treatment with glucocorticoids. You may want to continue therapy with close monitoring as long as the patient's clinically stable and appropriate for continuation of treatment.

For grade 2 or symptomatic interstitial lung disease, initiate appropriate treatment for that. Hold abemaciclib or ribociclib until this improves, until at least a grade 1, and then resume at the next lower dose with close monitoring.

And we should permanently discontinue the CDK4/6 inhibitor for any grade 3 or higher cases of interstitial lung disease.

[00:27:39]

Managing Palbociclib-Induced ILD

Now for palbociclib, for any new or worsening respiratory symptoms, interrupt treatment and evaluate the patient. You may want to initiate glucocorticoids as appropriate.

Dose modifications may not be indicated for grade 1 or 2 events, but palbo should be permanently discontinued in patients with severe ILD or pneumonitis, similar to the other 2 agents.

[00:28:12]

Key AEs With CDK4/6 Inhibitors: Monitoring and Prevention

This slide here is included for your reference. It's a summary of key recommendations for monitoring the more serious AEs associated with CDK4/6 inhibitors. You can reference back to this when you're starting patients on treatment in terms of how often you should be checking various labs, EKG, and guidelines just for symptoms the patients may report while they're on treatment.

[00:28:43]

Dose Reduction Studies of CDK4/6 Inhibitors

Often patients express reluctance to pursue a dose reduction when recommended for management of the toxicity on treatment. From what we found across clinical trials for all 3 of the CDK4/6 inhibitors, dose reductions do not appear to affect the efficacy of the respective agent, and these are effective strategies to consider to support adherence to therapy and improve patient outcomes.

[00:29:12]

Sally and Choice of Adjuvant CDK4/6i Therapy

All right, so let's briefly revisit our case and consider how adverse effects and patient comorbidities for each CDK impact our choice of therapy.

Recall that Sally is a 58-year-old Black female. She has stage III right breast cancer, so she's already higher risk with a T3N2 disease. She underwent right mastectomy, received adjuvant docetaxel and cyclophosphamide for 6 cycles, and then adjuvant radiation.

She's here today to talk about endocrine therapy with a CDK4/6 inhibitor. And as we recall, she has a past medical history that's significant for hypertension, and she's on hydrochlorothiazide and verapamil, which is a strong CYP3A inhibitor.

At baseline, she does have some mild neutropenia with a neutrophil count of 1.3, but her electrolytes, EKG, kidney-liver function all looks good.

[00:30:17]

Awareness of Comorbidities That May Affect CDK4/6i Treatment Selection and Initiation

So particular patient comorbidities that affect which treatment I'm likely to select for my patient are included here. I would avoid abemaciclib for any patient with known history of VTE or PE. I'd be reluctant to select ribociclib for any underlying cardiac arrhythmia. And I'd be cautious to select either palbo or ribociclib for a patient with baseline renal or hepatic dysfunction, as you see these more often with those 2 agents over abemaciclib.

[00:30:51]

Drug–Drug Interactions Among CDK4/6 Inhibitors

We also need to consider the concomitant medications our patient is using when selecting appropriate therapy, primarily the CYP3A inhibitors and inducers. But let's also be mindful of the substrates of CYP3A4 with palbo and ribo.

[00:31:15]

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

This slide is a summary of commonly used medications that may be contraindicated with CDK4/6 inhibitors given the drug-drug interactions. I just want to point out that both grapefruit juice and verapamil are CYP3A inhibitors and should be avoided with all 3 of these agents.

[00:31:34]

Monitoring Patient-Reported Symptoms

So coming back to our case, the pertinent positives are listed here in bold. She's postmenopausal female. She has stage III disease. We know off the bat she's eligible for both ribo and abemaciclib. She has hypertension and is on a strong CYP3A inhibitor for this condition. And she has a baseline mild neutropenia.

Given the neutropenia and higher stage of disease, I would consider abemaciclib, given it causes less neutropenia than ribociclib and carries less risk of cardiac toxicity. However, I would reach out to her cardiologist prior to starting any treatment to see if there is an appropriate alternative to verapamil for the management of her hypertension and if it was medically reasonable to consider changing her treatment for hypertension. If so, then I would initiate the CDK4/6 inhibitor with close monitoring.

[00:32:36]

Monitoring Patient-Reported Symptoms

This slide just provides a summary of signs and symptoms related to common AEs experienced with CDK4/6 inhibitors that patients should be advised to report at any point on therapy. So again, any fever or illness that occurs on treatment, diarrhea not controlled by medications, new or worsening cough, shortness of breath, wheezing, or fever, skin rash that's rapidly progressing, sores on the skin or mouth, unilateral pain or swelling in the arms or legs, new palpitations or episodes of chest pain or dizziness, as well as nausea or vomiting not controlled by medications.

[00:33:14]

Tools and Resources for Nurses Managing Patients Receiving CDK4/6 Inhibitors

Lastly, CCO has created a couple of resources you may find helpful in your practice when managing patients on CDK4/6 inhibitors. These have been developed by breast cancer experts and offer guidance on managing adverse events in specific case scenarios. You can click on the QR codes here for access and more information.

Let's Vote!

[00:33:35]

All right, so we're going to head back to some questions.

[00:33:38]

Pretest 2: A 56-yr-old woman with HR+/HER2- metastatic breast cancer has been taking ribociclib with an aromatase inhibitor for 2 mo. At a follow-up visit, she reports ongoing fatigue and nausea and admits that she has missed several doses of ribociclib due to her symptoms. Laboratory values are within normal limits. In your current practice, how would you counsel this patient to improve her treatment adherence?

Amy Goodrich: Okay, great. So here's a pretest. So, 56-year-old woman, HR+/HER2- metastatic breast cancer. She's been taking ribociclib with an aromatase inhibitor for 2 months. At follow-up, she reports ongoing fatigue and nausea and admits that she has missed several doses of her ribociclib due to her symptoms. Labs are normal in your current practice. How would you counsel this patient to improve her treatment adherence?

1. Counsel her to double her dosing if she misses a dose;
2. Encourage her to stop the ribociclib until the fatigue improves;
3. Recommend taking ribociclib at night with a light snack;
4. Suggest switching to abemaciclib as she may tolerate that better.

Okay, let me find this one. I'm sorry about that. So our number one answer is letter C at 67%.

I don't know if either of you want to say something about that at this point or keep going on. Well, let me get through the questions, and if you want to make comments about any of these, that's great.

[00:35:04]

Pretest 3: A 72-yr-old with HR+/HER2- metastatic breast cancer is taking abemaciclib plus fulvestrant. At her 1-mo follow-up, she says she feels overwhelmed by the number of medications she's taking and is also concerned about the out-of-pocket cost of her cancer treatment. She is thinking about stopping therapy. In your current practice, how would you counsel this patient?

So another pretest. A 72-year-old lady, also HR+, HER2 negative, metastatic breast cancer, taking abemaciclib with fulvestrant. At her 1-month follow-up, she says she feels overwhelmed by the number of meds she's taking. She's also concerned about the out-of-pocket cost, which is a real issue for patients. She's thinking about stopping therapy. In your current practice, how would you counsel this patient?

1. Ask her which medications feel burdensome and suggest a specialty pharmacy support;
2. Reassure her that feeling overwhelmed is normal and advise continuing treatment;
3. Recommend a reduction in dose of abemaciclib to reduce the burden and cost, or
4. Recommend delaying the next cycle until insurance issues are clarified.

And so already the vast majority, 70%, are up to you ladies to either discuss or keep moving along, whichever you'd prefer.

Elizabeth Diaz: Thank you, Amy. Yeah, I think we'll discuss the rationale for those closer to the end.

Promoting Adherence to and Persistence With CDK4/6 Inhibitor Therapy

[00:36:24]

So Julie covered the side effects of the CDK4/6 inhibitors very well. So now let's turn to talk about adherence.

[00:36:33]

Key Considerations for CDK4/6 Inhibitor Treatment

There we go. So these agents are, despite all those slides, are very well tolerated, and they've really transformed the treatment landscape for HR+/HER2- breast cancer.

These are some things to keep in mind when you're talking to your patients about adherence that they've doubled progression-free survival in metastatic disease and improved outcomes in early-stage disease. It's important to remember that early discontinuation can lead to worse outcomes and decreased quality of life. The dose adjustments can help patients stay on treatment, and efficacy is maintained even when dose reductions are required.

So now let's look at some of the data.

[00:37:16]

Treatment Discontinuation of CDK4/6 Inhibitors Due to AEs by Age Group

So this is the discontinuation rates in the metastatic setting for all 3 drugs. And for patients under 65, about 13% stopped palbociclib, 15% for ribociclib, and about 8%-9% for abemaciclib.

But the rates kind of double for patients over 65 and across all 3 drugs, as you can see them trend as their age increased. And the highest rates of discontinuation we're seeing with ribociclib followed by abemaciclib and then palbo. So in practice, we may underestimate this since patients who stop therapy are less likely to return for follow-up.

[00:37:58]

monarchE: Abemaciclib Discontinuations

And then in earlier-stage disease, this is information from the monarchE trial that shows that discontinuation rates are actually much higher in the early breast cancer setting. So it's about 40% in the monarchE trial. Now we see this across cancer types, and this may be because patients kind of struggle to appreciate the preventative intent of adjuvant treatment since they don't have any disease.

In this trial, about 50% of patients stopped treatment because of side effects. And it tends to happen very early, within the first 5 months. So this kind of highlights the importance of providing strong early support and scheduling frequent visits to stay ahead of the side effects.

[00:38:45]

TRADE: Phase II Dose-Escalation Trial of Abemaciclib + ET in HR+/HER2- EBC Planned for Adjuvant Abemaciclib

Also, there was a trial done out of Dana-Farber that's called the TRADE trial to see if gradually increasing the abemaciclib dose would improve tolerability. And so they started patients low, at 50 mg twice a day. And every 2 weeks, they escalated the dose up to the full 150 mg twice a day.

At 12 weeks, they had 70% of patients reach and maintain the full dose, and 93% were still on treatment. So overall, the discontinuation rates were much lower than what we saw in the monarchE trial. And it suggests an advantage to possibly starting low, especially in elderly or frail patients. But 1 limitation on this study was the small sample size, with only 90 patients. And I think we just need longer follow-up to see if that tolerability was sustained.

[00:39:40]

monarchE: Dose Reductions and Efficacy of Adjuvant Abemaciclib

So based on trial data, we know that about 30% of patients will need a dose reduction. But I think the key question is, will this affect the efficacy? And the short answer is no. I know I have several slides about abemaciclib, but we've seen similar trends in the data for ribociclib, that, I think, and palbo that Julie referred to earlier.

But in monarchE, about 40% of patients required dose reductions, and 60% had interruptions. The adjusted total dose that patients received is called the relative dose intensity, or RDI. At 4 years, invasive disease-free survival was essentially the same, whether the RDI was low at less than 66%, 66-93%, or they were able to maintain the full dose for most of the time above 93%. And the higher dose was the green line. And you can see how all the lines converge there, which in this case is a good thing, meaning that lowering the dose did not reduce the benefit.

[00:40:46]

Factors Affecting Breast Cancer Medication Adherence

So in addition to side effects, there are some other factors that affect adherence.

Older patients may struggle with complex regimens, other patients may not fully understand the importance of treatment, and financial barriers and language differences also can play a role. All of these highlight the need to individualize support for each patient.

[00:41:12]

Measures to Increase Oral Oncology Treatment Adherence

And so what are some ways we can improve adherence?

Well, some practical strategies include a drug diary or daily checklists, can also encourage patients to keep medications visible and involve their family for reminders. Some patient-initiated tools, like phone alarms or apps, and healthcare provider-initiated reminders, such as text messages or calls, can be effective. Overall, combining some of these approaches helps integrate medication taking into daily routines and can support better adherence.

[00:41:48]

Optimizing Education and Communication

Adherence is also strengthened through clear education and communication. These are some tips to assess readiness, involve caregivers, and set expectations about treatment and side effects, which can encourage them to participate in support groups.

And additionally, the financial burden of treatment cannot be overstated, as it often leads to delay in care. Therefore, it's essential to utilize patient assistance programs offered by the drug companies and specialty pharmacies and provide patients with written information to help them stay on therapy.

[00:42:32]

Key Differences With Abemaciclib, Palbociclib, and Ribociclib

So now I'm going to transition into kind of a summary discussion about how we can practically apply some of these approaches in clinic.

And this was a slide we've already seen, just a reminder about abemaciclib, you know, having the higher GI burden with an entire incidence of diarrhea to remind patients about the early use of loperamide. And if patients are struggling with nausea, it is best to take medications at night with a light snack.

For ribociclib, don't forget about the potential for QTc prolongation, which leads to arrhythmias and the need to get the EKGs at baseline and day 14 of the first cycle. And for palbo and ribociclib, they have a higher risk of neutropenia. And so we need to be monitoring their labs.

So Julie, how well do your patients tolerate the CDK4/6 inhibitors, and how do these differences impact your treatment decisions?

Julia LaBarbera: Yeah, generally, I feel like patients do pretty well on our CDK4/6 inhibitors, but I think a lot of that has to do with appropriate drug selection and sort of the underlying, you know, comorbidities the patient may experience. You know, if I have a relatively fit, good performance-status patient who I think can tolerate abemaciclib, I think that's something that I would suggest for them over the other 2, compared to, you know, a more elderly or more frail individual who has multiple comorbidities or perhaps mobility challenges that I would be very reluctant to be causing significant diarrhea in.

So with ribociclib and palbociclib, I think some of the data from these clinical trials do show pretty good quality of life on these 2 agents. So I tend to lean a little bit more towards 1 of these 2 or even palbociclib when I have a patient that I'm more worried about, you know, tolerability of adding these drugs and, you know, what's going to be the most effective strategy to get them to maintain their treatment.

What about in your practice?

Elizabeth Diaz: Yeah, absolutely. I think whether they're on abemaciclib if the patient's, you know, elderly or frail, we wouldn't use it just because of our concern for dehydration. I agree with that. Absolutely.

One other thing I think to watch out for is if they do have some kind of immunosuppression, maybe HIV transplant patient, maybe they're on an immunosuppressant for an autoimmune illness, you know, then I wouldn't use probably palbo or ribo because of the neutropenia risk. I know, okay, I know we don't really see serious infections, but something to watch out for, and I've seen, is maybe patients will have trouble with, like, a chronic UTI or some type of chronic infection they're having trouble to get over.

And I always, you know, always remind patients if they are seeing someone else and they end up on antibiotics for an infection to stop their cancer treatment, you know, obviously call us, but especially stop their cancer treatment, that having a 2-week or even 1-month delay to get over an infection is more important. And over time they'll, they'll tolerate treatment much better.

Julia LaBarbera: Absolutely. Yeah.

Elizabeth Diaz: Okay. So next – why isn't this –

[00:46:10]

Barriers to Care: Factors Influencing Adherence

So moving in – back to the adherence and barriers to care. This is actually a list from the World Health Organization of specific barriers to care that can influence adherence and kind of summarizes what I've already discussed, where some patient-related issues include, you know, the perception of the treatment benefit, forgetfulness, and mental health challenges. Some therapy-related barriers include, of course, the side effects, complexity and duration of treatment, other disease-related factors, such as more than 4 comorbidities or advanced disease can play a role.

And they also included the healthcare system here. Some data showing that, of course, if they're shorter visits that may not allow for appropriate education and communication. They include prescribing your errors and a lack of shared decision-making, which can decrease adherence. Also to keep in mind that social and economic factors like younger or older age, high cost, and education level can further influence adherence.

[00P:47:16]

Strategies to Address Potential Barriers to Care

There are some ways that we can help. These are some strategies to help patients overcome these barriers, ensure satisfaction with treatment by managing those side effects or lowering the dose, improve satisfaction with communication, making sure patients feel understood and respected. And finally, we should assess the patient's resources, support system, and ability to attend visits to promote better adherence.

And so, Julie, I'll go back to you again. What are some barriers that you commonly see in your practice?

Julia LaBarbera: I think cost is a big 1. I actually am trying to start a patient on 1 of the CDK4/6 inhibitors. She has a federally funded insurance plan, and her out-of-pocket cost for this drug is $1,800 per month, which she just can't afford.

And so we're exploring all potential options from, like, grant support to patient assistance. But it's really distressing because, unfortunately, she has multiple comorbidities. And so we really are relying on systemic therapy to manage her disease.

I think another big 1 is healthcare literacy. You know, we haven't addressed this in much detail, but the dosing schedule of the CDK4/6 inhibitors is an important factor to consider. You know, abemaciclib is given twice a day continuously throughout the month, whereas palbo and ribo are taken daily for 3 weeks on and about 7 days off.

So, you know, kind of stressing the importance of why we're recommending these dosing schedules and making sure the patient understands the implications, particularly with ribo and palbo, of the importance of that time off of treatment to allow the white blood cell counts to recover. So that can be a challenge to kind of get people to understand, you know, the schedule as compared to just taking a pill once a day like endocrine therapy.

What are some of the barriers you’re encountering?

Elizabeth Diaz: Yeah, we also struggle with the financial burden of it all with our patients too and get them, you know, connected with our financial counselors and patient assistance programs. But I think it just kind of goes into this idea of just about how cumbersome the entirety of cancer treatment can be for our patients because they, you know, not only have to deal with the side effects, and like you said, learning the regimens, but just transportation to all the appointments can be challenging here where I am in San Antonio, as well as, like you said, the financial aspect of it all.

Julia LaBarbera: Absolutely.

[00:50:14]

Multidisciplinary Team Approach to the Management of Patients With Breast Cancer

Elizabeth Diaz: So 1 thing that can help us a little bit is not forgetting that this is a team approach, that a multidisciplinary approach can often provide the best outcomes. Oftentimes for patients with metastatic disease, I'll send them to palliative care, and for my elderly patients, to geriatrics, where this may be more valuable, kind of have 1 provider that could address multiple needs.

I think it's also important to maximize that team approach when we see them in clinic. It's kind of, to me, the blue circle where I'm fortunate enough at my practice to have pharmacists, nurses, social workers, and even navigators that help us deliver chemo education and help with the coordination of care.

[00:50:56]

Interventions to Improve Adherence

This is a good summary of some adherence strategies.

You know, adherence can be difficult to measure. Patients are probably not – they're probably reporting taking more medications than they actually do. So I think having honest conversations with them is critical, and there's not 1 single strategy that can be effective, but I think we've gone over this a lot already about providing some written information, using those resources.

And I think under the patient-related interventions there, it's key to consider their psychological needs, whether that means they might need a prescription for an SSRI or SNRI, or even a referral for behavioral therapy. I've seen that help my patients just tremendously, even with compliance.

[00:51:48]

Optimal Strategies to Partner With Patients in Their Care

Other strategies that I use, again, include letting them know, you know, the duration of treatment and our expectation for treatment early on in our discussions and the importance of proactive communication.

I think I have about – at least 1 patient a week that they've been in the ER or been admitted to the hospital, but they never called us. And that can be frustrating because if we had told them to stop their therapy, maybe they wouldn't have ended up in the ER.

So what are some strategies that you use in your practice to help promote education?

Julia LaBarbera: We are lucky enough to have a nurse navigator at our site, as well as APPs that assist our physicians. So we are able to spend a good amount of time doing pretreatment education with the patients in terms of, you know, side effect management, goals of therapy, duration of treatment, etc.

I have noticed, more specifically with the drug manufacturers, that they seem to have pharmacy teams that will actually reach out to the patients, maybe a little bit more than my own pharmacy team does. But some patients find that to be a very valuable resource, as well, just for answering some questions upfront. And as a healthcare provider, if I'm experiencing a side effect or toxicity that maybe I don't see very often, it's always nice to kind of loop in our pharmacy team and kind of get a better understanding of pharmacodynamics and kinetics that maybe I'm not always as familiar with.

But I think also with the improvements in the electronic medical record and sort of the ease of being able to contact your provider, like we have the MyChart messaging system. I find a lot of patients feel really encouraged and empowered to reach out with their questions through that app, which I think just kind of helps sort of more for, like, the day-to-day flow of getting through treatment. And if they've got something coming up more urgently or – or unexpectedly, then they can just reach out to us more quickly.

Elizabeth Diaz: Yeah, I agree. We have MyChart as well, and that is extremely helpful.

[00:54:19]

Patient Resource: Navigating Your Journey With CDK4/6 Inhibitors

And CCO actually provides this resource to help patients navigate their cancer journey.

It's a 2-page, kind of easy-to-understand resource that you can share in your clinic. It has tips on navigating treatment, what to expect, and specifically when patients should call their care team.

And now I'll turn this back over to Amy for the posttest questions.

[00:54:42]

Posttest 2: A 56-yr-old woman with HR+/HER2- metastatic breast cancer has been taking ribociclib with an aromatase inhibitor for 2 mo. At a follow-up visit, she reports ongoing fatigue and nausea and admits that she has missed several doses of ribociclib due to her symptoms. Laboratory values are within normal limits. In your current practice, how would you counsel this patient to improve her treatment adherence?

Amy Goodrich: Great. Thank you. So posttest number 2 is our 56-year-old with HR+/HER2- metastatic breast cancer.

She's been on ribociclib and an aromatase inhibitor for 2 months. She has nausea and fatigue. She's missing doses. Labs are normal. And so what would you counsel this patient to improve her adherence?

1. Counsel double her dose;
2. Encourage her to stop until the fatigue improves;
3. Recommend taking her ribociclib at night with a light snack; or
4. Suggest switching to abemaciclib as she may tolerate that better.

And C is 80% of our responses, and it looks like that is the correct answer.

I want to keep moving along here because I want to have time for questions as well.

[00:55:48]

Posttest 3: A 72-yr-old with HR+/HER2- metastatic breast cancer is taking abemaciclib plus fulvestrant. At her 1-mo follow-up, she says she feels overwhelmed by the number of medications she's taking and is also concerned about the out-of-pocket cost of her cancer treatment. She is thinking about stopping therapy. In your current practice, how would you counsel this patient?

We've got a 72-year-old. She's got metastatic breast cancer. She's on abemaciclib. At her 1-month follow-up, she's overwhelmed. She's concerned about her out-of-pocket costs. She's thinking about stopping therapy. In your practice, how would you counsel this patient?

1. Ask which medications are burdensome and suggest a specialty pharmacy for support;
2. Reassure her that being overwhelmed is normal and to just forge on continuing treatment;
3. Recommend a reduction in the dose of abemaciclib to reduce the burden and cost; or
4. Delay the next cycle until her insurance issues are addressed.

And so, A is our overwhelming answer, and that is absolutely correct. Those specialty pharmacies can be very, very helpful.

[00:56:44]

Poll 4: Do you plan to make any changes in your clinical practice based on what you learned in today's program?

And then do you plan to make any changes in your clinical practice based on what you've learned today?

And that's a quick yes, no.

[00:56:51]

Poll 5: Please take a moment to text in 1 key change that you plan to make in your clinical practice based on this education.

And then please take a moment to click in anything that you plan to change based on this education.

Q&A

Amy Goodrich: And so I'm going to ask 1 question just because we're out of time. I'm just going to pick 1 question. So if you start a patient on adjuvant abemaciclib and they can't tolerate it, and you switch to ribociclib, would you count the time they were on abemaciclib toward their 3 years? Or would you start all over again 3 years from the ribociclib?

Elizabeth Diaz: Yeah, I can take that question. We would count all of that as their 3 years. We wouldn't start the clock over again.

What about you, Julie?

Julia LaBarbera: Same. We wouldn't start the clock over again for that.