Assistant Professor, Department of Hematology & Oncology Pharmacy Mayo Clinic, Rochester, MN
Breast cancer is the most common cancer in women and remains a leading cause of cancer-related morbidity, mortality, and resource utilization. For patients with advanced breast cancer, prognosis remains especially suboptimal, primarily because of acquired pharmacologic resistance.
Fortunately, several new drugs and drug combinations have recently become available. Specifically, the class of drugs that utilize cyclin-dependent kinase (CDK)4/6 inhibitors is frequently incorporated into first-line treatment of patients with postmenopausal, hormone receptor–positive (HR+)/HER2− advanced breast cancer.
Abemaciclib is the newest CDK4/6 inhibitor approved by the US Food and Drug Administration. Mechanistically, abemaciclib more potently inhibits CDK4/cyclin D1 and CDK6/cyclin D3 than either palbociclib or ribociclib1 and is more selective for CDK4 than for CDK6.2 The clinical implications of these mechanistic differences remain to be determined regarding their impact on efficacy, but these differences appear to explain the differing adverse effect (AE) profiles of these 3 drugs. In addition, abemaciclib has been shown to cross the blood–brain barrier, whereas palbociclib and ribociclib do not.3 Whether abemaciclib may be helpful in treating patients with brain metastases or in reducing the likelihood of developing brain metastases is an important question being evaluated in clinical studies.
Palbociclib and ribociclib have been studied in thousands of patients throughout the PALOMA4,5 and MONALEESA6,7 series of clinical trials, with predominantly consistent results. Abemaciclib has demonstrated clinical efficacy with a generally tolerable safety profile in the MONARCH 1, 2, and 3 clinical trials.1,8,9 An exploratory analysis of the MONARCH 2 and MONARCH 3 data sets was recently performed to determine whether patient and disease characteristics may be defined to assist in optimizing treatment strategies with abemaciclib.10 The findings showing substantial benefit from treatment with abemaciclib in a group with poor prognosis, including those with hepatic metastases, progesterone receptor–negative tumors, or high-grade tumors, are intriguing but should be viewed as hypothesis-generating at this time.
In the absence of head-to-head comparisons, differentiating factors may include cross-study evaluation of efficacy as well as of AE profiles; dosing and administration considerations; drug interactions; and cost. All 3 CDK4/6 inhibitors are indicated as combination therapy with an aromatase inhibitor as initial therapy.11-13 Both palbociclib and abemaciclib are indicated as combination therapy with fulvestrant following progression on endocrine therapy in postmenopausal HR+/HER2− advanced or metastatic breast cancer.11,13 However, abemaciclib is the only CDK4/6 inhibitor currently indicated as monotherapy following progression on endocrine therapy and chemotherapy,13 with a response rate of approximately 20%.14
The most common dose-limiting AE of palbociclib and ribociclib is neutropenia, whereas diarrhea is most predominant with abemaciclib.14 Neutropenia or thrombocytopenia may occur with any of the CDK4/6 inhibitors and requires monitoring. Ribociclib, as well as abemaciclib, may cause elevation in liver function tests, also warranting monitoring. QTc prolongation is possible with ribociclib, and electrocardiograms and serum electrolyte monitoring are therefore recommended to reduce the risk for complications. Fatigue is another noteworthy AE of CDK4/6 inhibitors, including abemaciclib.14 Whereas management of the AEs related to the use of CDK4/6 inhibitors generally includes withholding or reducing doses or providing symptom management, between 5% and nearly 20% discontinuation rates have been reported across clinical trials.
All of the CDK4/6 inhibitors are hepatically metabolized, primarily by the CYP3A enzymes.14 Patients receiving strong CYP3A inhibitors or inducers, as well as sensitive CYP3A substrates, must be evaluated closely. Specific risk mitigation strategies may include dose modification or avoidance of concomitant use, depending on the particular medications involved.14
Another distinguishing feature of CDK4/6 inhibitors is their dosing schedule. Whereas palbociclib and ribociclib are administered once daily for 21 consecutive days of a 28-day cycle,11,12 abemaciclib is administered twice daily continuously.13 Palbociclib is dosed as a single capsule taken with food.11 Depending on tolerability, concomitant medications, and hepatic function, the dose of ribociclib may be 1 to 3 tablets without regard to food intake.12 Finally, abemaciclib is dosed as a single tablet most frequently given twice daily without regard to food, with the exception being in patients with severe hepatic impairment, who receive the dose once daily.13
Currently, CDK4/6 inhibitors have an established role in the management of postmenopausal women with HR+/HER2− advanced or metastatic breast cancer. Ongoing studies in other breast cancer settings continue. Abemaciclib is the most recent entry into the CDK4/6 inhibitor class, with established efficacy and a unique toxicity profile. The question of whether there is a preferred CDK4/6 inhibitor for select subsets of patients remains to be answered. Future studies will better define the unique role and best overall value of palbociclib, ribociclib, and abemaciclib.
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