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Adj CDK4/6i Toxicities
How I Manage Key Toxicities With Adjuvant CDK4/6 Inhibitors for Early Breast Cancer

Released: December 22, 2023

Sarah Donahue
Sarah Donahue, MPH, NP
Joyce O'Shaughnessy
Joyce O'Shaughnessy, MD
Sara M. Tolaney
Sara M. Tolaney, MD, MPH
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Key Takeaways
  • Adjuvant CDK4/6 inhibitor therapy significantly improves invasive disease–free survival in patients with hormone receptor–positive, HER2-negative early breast cancer at higher risk, but adherence is challenged by treatment-related adverse events.
  • Patients experiencing abemaciclib-related diarrhea should be counseled to take loperamide and manage with dose modifications as needed.
  • Patients receiving ribociclib should be monitored for neutropenia, which is managed with dose modifications.

As a nurse practitioner specializing in breast cancer, I care for patients receiving either adjuvant abemaciclib or investigational adjuvant ribociclib through the phase III NATALEE trial. When given with endocrine therapy, both CDK4/6 inhibitors significantly prolong invasive disease–free survival vs endocrine therapy alone in patients with hormone receptor (HR)–positive, HER2-negative early breast cancer at a higher risk of recurrence.

Patients benefit the most when we quickly identify and manage adverse events (AEs). Below, I share guidance on managing the most common and challenging AEs: diarrhea with abemaciclib and neutropenia with ribociclib.

Managing Diarrhea With Adjuvant Abemaciclib
Diarrhea usually onsets approximately 1 week after starting abemaciclib. We manage this AE with supportive care and dose modifications. We counsel patients starting abemaciclib to take loperamide if they experience diarrhea and to contact us. In my clinic, patients message us through our electronic medical record system, MyChart, or call the triage nurses. The triage nurses monitor MyChart messages and help patients with initial management; if the diarrhea becomes too complicated, they bring us in to help.

Abemaciclib-related diarrhea is usually low grade. Patients with grade 1 diarrhea (<4 episodes over baseline per day) can continue abemaciclib and should take loperamide. I counsel patients that the instructions for over-the-counter loperamide are intended more for viral gastroenteritis and do not account for severity. We recommend starting with 1 loperamide tablet at the first episode—rather than 2 tablets per the package insert—and taking 1 tablet for each subsequent episode. We also counsel that patients can take up to 8 tablets in a 24-hour period instead of the maximum of 4 tablets listed in the package insert.

If the patient has higher-grade diarrhea (eg, explosive, watery, and/or ≥4 episodes over baseline a day), I hold abemaciclib and counsel them to take 2 loperamide tablets for the first episode and 1 tablet for subsequent episodes to get the diarrhea under control. Then, I decide whether they need a dose reduction. Patients with grade 2 diarrhea (4-6 episodes over baseline per day) can resume their regular abemaciclib dose. Those experiencing grade 3 diarrhea (≥7 episodes over baseline per day) get dose reductions. 

In both monarchE and the abemaciclib prescribing information, the starting dose is 150 mg twice daily. The next dose level is 100 mg twice daily. We modify that recommendation if patients are very worried about their cancer or experiencing slightly more than moderate, but not extreme, diarrhea. For these patients, we recommend 150 mg for their first daily dose and 100 mg for their second daily dose. If the diarrhea continues and/or there are other symptoms (eg, fatigue, some nausea), then I dose reduce to 100 mg twice daily.

Managing Neutropenia With Adjuvant Ribociclib
Adjuvant ribociclib is still investigational, so I will share my experience from my center’s participation in the ongoing NATALEE trial. Neutropenia is the most common and challenging AE, even with adjuvant ribociclib given at 400 mg/day instead of the 600-mg dose approved for metastatic disease. Despite this lower dose and the younger age of patients with early disease, I saw more neutropenia in the early vs metastatic setting. NATALEE participants have higher-risk disease and had often recently received neoadjuvant chemotherapy and potentially radiation therapy. These recent exposures made them more prone to myelosuppression, in particular neutropenia, when starting adjuvant ribociclib. That being said, my patients starting adjuvant ribociclib at 400 mg experienced less gastrointestinal toxicity (eg, diarrhea or queasiness, especially during the first cycle) than my patients starting 600 mg for metastatic disease.

We manage neutropenia with monitoring and dose modifications. Adjuvant ribociclib is given for 21 days on/7 days off, and we draw labs after 7 days off ribociclib. I prefer to draw labs on the seventh or eighth day—technically, the start of the next cycle—because the absolute neutrophil count (ANC) improves even within 1 day since CDK4/6 inhibitors induce cell cycle arrest, but not death, of neutrophil precursors. During the first 2-3 cycles, I find it helpful to discuss dosing with patients using a physical, laminated calendar. I specifically ask, “What day did you start the medication?” and “When was your last pill?” Patients often miss a day and add another day at the end of the cycle, which affects their labs. I find dosing a little easier with abemaciclib, which is dosed continuously.

If their ANC is <1000/mm3 (grade 3), we hold ribociclib. If the ANC is approximately 900/mm3, recovery sometimes just takes 1 day, but an ANC around 700/mm3 usually needs several days. If this is the patients’ first neutropenic episode, we wait longer to learn how quickly they tend to recover. 

Once patients are tolerating therapy, know when they will get labs, and know how to contact us about AEs, then we can draw labs less often after the first 6 cycles. Per the prescribing information for metastatic disease, you do not have to monitor blood counts every cycle after 6 cycles if the patient is doing well and has not had dips. In practice, I prefer to check counts at least every 2-3 cycles.

Your Thoughts?
Which AEs do you find the most challenging to manage with adjuvant CDK4/6 inhibitor therapy? Answer the polling question and join the conversation by posting a comment in the discussion box.

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