A Review of CDK4/6 Toxicities and Interactions Management in Breast Cancer

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CDK4/6 inhibitors are tolerated fairly well in patients with cancer.
CDK4/6 inhibitors are tolerated fairly well in patients with cancer.

An overview of potential drug interactions and adverse effects as seen in the use of cyclin-dependent kinase (CDK) 4/6 inhibitors in patients with breast cancer, published in The Oncologist, addresses management strategies that can be applied in clinical practice.

CDK4/6 inhibitors are tolerated fairly well in patients with cancer. The agents work by blocking the activity of regulatory enzymes, preventing cell division and tumor growth.

Currently, palbociclib in combination with letrozole is approved as first-line therapy for metastatic hormone receptor (HR)-positive breast cancer and in combination with fulvestrant as second-line therapy.

Ribociclib is approved for first line therapy of metastatic HR+ breast cancer in combination with any aromatase inhibitor, and the FDA has granted abemaciclib Breakthrough Therapy designation.

Palbociclib/ribociclib should not be administered with concomitant strong CYP3A inhibitors; if this is unavoidable, the dose should be reduced. Strong CYP3A4 inducers should also be avoided as this can reduce the plasma concentration of palbociclib/ribociclib. Plasma concentrations of CYP3A4 substrates with a narrow therapeutic index may increase if coadministered with palbociclib/ribociclib.

Abemaciclib should not be concomitantly administered with strong CYP3A4 inducers or inhibitors.

The most frequently observed adverse events with palbociclib/ribociclib were hematologic, with neutropenia occurring most often. However, unlike chemotherapy induced-neutropenia, CDK4/6-induced neutropenia is rapidly reversible.  CDK4/6-induced neutropenia should be managed with supportive care and dose adjustments.

Abemaciclib has a lower incidence of neutropenia, but fatigue and gastrointestinal adverse events occur at a higher frequency.  Nausea and vomiting can be treated with standard antiemetic therapies, such as prochlorperazine, metoclopramide, serotonin 5-HT3 antagonists, and haloperidol, but may cause QT prolongation if coadministered with the CDK4/6 inhibitors. ;

The investigators concluded their review noting that a better understanding of the toxicity profile is needed to develop management strategies that minimize drug interruptions optimizing therapeutic efficacy for patients with breast cancer.

Reference

1. Spring LM, Zangardi ML, Moy B, Bardia A. Clinical management of potential toxicities and drug interactions related to cyclin-dependent kinase 4/6 inhibitors in breast cancer: practical considerations and recommendations [published online July 13, 2017]. Oncologist. doi: 10.1634/theoncologist.2017-0142

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