Managing Side Effects of CDK4/6 Inhibitors in Breast Cancer

Stephanie Graff, MD, FACP, FASCO Brown University Cancer Center | Rahul Gosain, MD, MBA Wilmot Cancer Institute | Rohit Gosain, MD Roswell Park Comprehensive Cancer Center

Key Points

• Ribociclib, abemaciclib, and palbociclib are approved CDK4/6 inhibitors for the treatment of metastatic hormone receptor-positive (HR+) breast cancer.

• Ribociclib and abemaciclib have expanded into early-stage disease, while palbociclib is primarily used in combination with inavolisib in the metastatic setting.

• Abemaciclib is associated with more prominent diarrhea as a treatment-related adverse event, and supportive care is necessary to prevent secondary complications.

• Interstitial lung disease (ILD) and pneumonitis are rare, class-wide side effects of CDK4/6 inhibitors, and should prompt a treatment change if identified.

CDK4/6 Inhibitors

On the Oncology Brothers podcast, Stephanie Graff, MD, FACP, FASCO, of Brown University Cancer Center, joined Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, to discuss managing the toxicities associated with the approved CDK4/6 inhibitors in breast cancer: ribociclib, abemaciclib, and palbociclib.

All three agents are approved for HR+ metastatic breast cancer, but more mature, robust data for ribociclib and abemaciclib have led to decreased usage of palbociclib, except in combination with inavolisib per the phase 3 INAVO120 trial. Moreover, data from the NATALEE and monarchE trials have brought the use of ribociclib and abemaciclib into the early-stage and adjuvant settings. Of the two, ribociclib has slightly broader eligibility criteria, said Dr. Rahul Gosain.

Ribociclib Side Effects

The approved starting doses for ribociclib are 400 mg once daily in the adjuvant setting and 600 mg once daily in the metastatic setting. The dose can be reduced to 200 mg once daily. The most common toxicities for ribociclib include fatigue, anemia, leukopenia, thrombocytopenia, nausea, diarrhea, alopecia, transaminitis, peripheral edema, and QTc interval prolongation. To monitor for QTc prolongation, the recommendation is a baseline electrocardiogram (ECG) and another ECG at 1 month. 

QTc prolongation is most likely related to drug-drug interactions, and can even be driven by holistic therapies like grapefruit juice and St. John’s wort, Dr. Graff said. Additionally, medications for nausea like ondansetron can lead to prolonged QTc interval, and more routine ECG testing should be done when these supportive agents are used.

Overall, data show that reducing ribociclib from the starting dose to manage side effects does not significantly worsen outcomes, so reductions, holds, or other modifications should be considered for patients experiencing high levels of toxicity.

Abemaciclib Side Effects

The recommended starting dose for abemaciclib is 150 mg twice daily when combined with endocrine therapy, or 200 mg twice daily when used as a monotherapy. The dose can be reduced by 50 mg at a time down to a minimum of 50 mg twice daily. Diarrhea is the most prominent side effect of abemaciclib, and other associated toxicities include fatigue, abdominal pain, leukopenia, neutropenia, anemia, thrombocytopenia, alopecia, transaminitis, decreased appetite, pneumonitis, and venous thromboembolism (VTE). Similar to ribociclib, reducing the dose of abemaciclib is associated with decreased toxicity burden. 

Diarrhea occurs in the majority of patients, and may be the driver behind abdominal pain and decreased appetite events. Diarrhea-related dehydration may also drive fatigue, though fatigue is generally seen as a class-wide feature of CDK4/6 inhibition as it is sensitive to dose modifications, said Dr. Graff. Elevated liver function parameters are seen with abemaciclib, though are not as common as with ribociclib. The risks of VTE and pneumonitis are low, but patients should be informed so they can report any potentially related symptoms.

“I do prescribe Imodium with the initial [abemaciclib] prescription so that patients have it at home; I don’t necessarily have them take it prophylactically, but I am very clear that I expect them to have diarrhea and I tell patients to take Imodium at their first sign of diarrhea,” Dr. Graff said. If diarrhea persists despite the use of loperamide (Imodium), patients should communicate that so their provider can take steps like giving extra fluids, checking potassium levels, intensifying management from loperamide to diphenoxylate/atropine (Lomotil), or implementing a treatment break and lowering the dose.

Choosing Between Ribociclib and Abemaciclib

Unless the patient only meets the slightly broader eligibility criteria for ribociclib and not abemaciclib, the choice between the two agents may come down to shared decision making with patients based on the slightly different side effect profile. “I have patients who don’t want to take ribociclib because they don’t want a risk of liver toxicity, and I have patients who had terrible diarrhea with their chemotherapy, and the idea of that being a side effect with abemaciclib is quite concerning for them,” said Dr. Graff. “Alternatively, I have patients who have chronic constipation, and they may choose abemaciclib, so it goes either way.”

The doctors noted upcoming presentations on overall survival data for abemaciclib at the 2025 European Society for Medical Oncology (ESMO) Congress. Longer-term follow-up data for ribociclib from NATALEE may impact the choice between these two agents. 

Palbociclib Side Effects

The recommended starting dose for palbociclib is 125 mg once daily, and the dose can be reduced to 100 mg or 75 mg once daily. The most common toxicities associated with palbociclib are fatigue, leukopenia, neutropenia, anemia, thrombocytopenia, transaminitis, nausea, diarrhea, rash, alopecia, decreased appetite, and ILD or pneumonitis. 

As with ribociclib or abemaciclib, patients with metastatic breast cancer on palbociclib should be made aware of the symptoms of ILD so they can report if they start to occur at any time during treatment. Additionally, cytopenias may be more profound with palbociclib compared with the other two CDK4/6 inhibitors, and may lead to more sweeping need for dose reductions. 

For patients on any CDK4/6 inhibitor, if CT scans reveal evidence of potential ILD, clinicians should partner with pulmonary colleagues and consider the clinical context of patients, their symptom profile, and the nature of their disease to make a determination on whether the presentation is a postviral symptom, disease progression, or truly a drug effect. For the most part, it’s straightforward to identify a history of infectious signs or symptoms or to determine evidence of disease progression to the lungs, and it may be the absence of either that indicates treatment-related ILD, said Dr. Graff.