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CDK4/6 inhibitor selection in metastatic breast cancer

CDK4/6 inhibitor selection

Abemaciclib, palbociclib and ribociclib are three CDK4/6 inhibitors approved for the treatment of HR+/HER2- locally advanced or metastatic breast cancer; but how do they compare and how will you decide on which CDK4/6 inhibitor to select for your breast cancer patient?

Abemaciclib, palbociclib and ribociclib are three cyclin dependent kinase (CDK)4/6 inhibitors that are US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved for the treatment of hormone receptor positive/human epidermal growth factor 2 negative (HR+/HER2-) metastatic breast cancer1–6

Abemaciclib is also FDA approved as a monotherapy for HR+/HER2- advanced breast cancer in patients who have progressed following endocrine therapy and prior chemotherapy treatment4.

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There are currently no clinical trials that directly compare the efficacy of the individual CDK4/6 inhibitors. Cross-trial comparison of efficacy should be avoided as there are clear differences in the patient populations assessed. 

Differences in patient populations include menopausal status, endocrine therapy sensitivity, prior treatments received and degree and location of metastatic spread (Table 1).

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There are noteworthy pharmacological differences between abemaciclib, palbociclib and ribociclib. All three are orally active agents that bind to the ATP clefts of CDK4 and CDK618. Palbociclib and ribociclib potencies are similar; however, palbociclib has greater affinity for CDK6 compared to ribociclib18. Abemaciclib is the most potent of all three inhibitors for both CDK4 and CDK6 (Table 2). Abemaciclib also has significant potency to CDK9 and is therefore considered to be less specific compared to palbociclib and ribociclib38

It is thought that this affinity to CDK9 may partly explain the clinical efficacy of abemaciclib as a monotherapy, and the higher levels of gastrointestinal toxicity observed for abemaciclib compared to ribociclib and palbociclib10,18.

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Abemaciclib, palbociclib and ribociclib are now considered standard of care for HR+/HER2- metastatic breast cancer, with overall increases in quality of life. They are all generally well tolerated; however, there are notable differences in the adverse events triggered by each CDK4/6 inhibitor, and in the level and type of monitoring required. 

These differences provide an opportunity to select a CDK4/6 inhibitor that is optimal for a patient based on the presence of comorbidities. Here, we discuss differences in adverse events and monitoring for each of the CDK4/6 inhibitors.

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Clinical trials have not yet identified any predictive markers for CDK4/6 inhibitor response in patients with HR+/HER2- metastatic breast cancer; however, it is an active area of research and interest. 

An understanding of predictive markers for CDK4/6 inhibitor response may one day enable better patient selection for treatment. A biomarker specific to any one CDK4/6 inhibitor may additionally inform on choosing the best CDK4/6 inhibitors for a patient.

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