What is abemaciclib?
Abemaciclib is a cyclin D kinase 4 and 6 inhibitor.
How does abemaciclib work?
Cyclin D kinase (CDK 4/6) leads to cell proliferation by promoting the transition from G1 to S phase of the cell cycle. Activation of CDK4 and 6 results in phosphorylation of the retinoblastoma protein (Rb) resulting in cell cycle progression and cellular proliferation. Abemaciclib inhibits CDK4/6 and thus inhibits cellular proliferation.
What is this approved for and what is the basis for this approval?
1. Abemaciclib, as a single agent at a dose of 200 mg BID, is approved for the treatment of women with refractory HR+/HER2- metastatic breast cancer after treatment with endocrine therapy (ET) and at least two types of chemotherapy. This was on the basis of the MONARCH 1 single-arm trial in which the objective response rate (ORR) was 19.7 percent (95% CI, 13.3-27.5; 15% not excluded), and the median progression-free survival (PFS) was 6 months (Clin Cancer Res 2017;23:5218-5224).
2. Abemaciclib, at the dose of 150 mg BID with standard dose fulvestrant, was approved for the treatment of women with HR+/HER2- advanced breast cancer after progression on ET. The MONARCH 2 trial compared abemaciclib/fulvestrant to fulvestrant alone. The median PFS seen was 16.4 months versus 9.3 months (HR 0.553; 95% CI, 0.449 to 0.681; P<0.001). The ORR was 48.1 percent (95% CI, 42.6% to 53.6%) compared with 21.3 percent (95% CI, 15.1% to 27.6%) in the control group (J Clin Oncol 2017;35:2875-2884).
Although not FDA-approved at this time, abemaciclib was also studied, at a dose of 150 mg BID along with letrozole or anastrozole versus letrozole or anastrozole alone as initial treatment in women with HR+/HER2- advanced breast cancer. The median PFS was significantly prolonged in the abemaciclib arm (HR, 0.54; 95% CI, 0.41 to 0.72; p=0.000021; median: not reached in the abemaciclib arm, 14.7 months in the placebo arm). The ORR in the abemaciclib arm was 59 percent versus 44 percent in the control group (p=0.004) (J Clin Oncol 2017;35:3638-3646).
How do you administer this drug?
Abemaciclib is given orally twice daily at about the same time each day. It can be taken with or without food. It should be taken whole and not crushed, chewed, or split. Patients should avoid grapefruit products.
Are there any premedications needed?
Antiemetics are not routinely needed.
What are the common side effects associated with abemaciclib (> or = 10%)?
The most common adverse effects (>50%) are fatigue, diarrhea, nausea, and increased serum creatinine (52-98% (grade 3/4=0.8-2%)).
Other common adverse effects (30-50%) are decreased appetite, abdominal pain, vomiting, anemia (grade 3/4=5%), decreased absolute lymphocyte count, neutropenia (grade 3/4=4%, neutropenic fevers 1%), increased LFTs, and infection.
Less common side effects (<30%) include headache, dizziness, alopecia, constipation, stomatitis, xerostomia, dysgeusia, thrombocytopenia (grade 3/4=4-6%), arthralgias, cough, fever, and dehydration.
Are there any important drug interactions I should be aware of?
Abemaciclib is largely metabolized by CYP3A4, and interactions with strong/moderate CYP3A4 inducers and inhibitors should be expected. It is contraindicated with strong CYP3A4 inducers, and there are specific dosage adjustments recommended if used with strong CYP3A4 inhibitors. If the dose of abemaciclib is 150-200 mg BID, it should be decreased to 100 mg BID. If the dose of abemaciclib is 100 mg BID, it should be decreased to 50 mg BID.
Abemaciclib can increase the levels of metformin.
How do I adjust the dose in the setting of renal insufficiency?
If CrCl > 30mL/min, no dosage change is needed. It has not been studied in CrCl < 30mL/min.
How do I adjust the dose in the setting of hepatic insufficiency?
In mild-moderate hepatic insufficiency (Child-Pugh class A or B), no adjustment in dosage is needed. In severe hepatic impairment (Child-Pugh class C), the frequency should be reduced to once daily.
Practical tips
When adjusting abemaciclib dose for toxicity (in monotherapy), each reduction should be a decrease by 50 mg BID to a minimum of 50 mg BID. Specific dosage reductions for diarrhea and for hematologic toxicities are available. Available in tablets of 50 mg, 100 mg, 150 mg, and 200 mg.
What should my patients know about abemaciclib?
Abemaciclib should not be given to pregnant women. A pregnancy test should be done prior to therapy and birth control should be used during and for 3 weeks after end of treatment. As with all oral cancer treatments, safe handling procedures are needed. Patients should report significant side effects and have blood tests done on time.
What useful links are available regarding abemaciclib?
* https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208716s000lbl.pdf
* https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm578071.htm
What else should I know?
Baseline labs should include CBC, LFTs, and pregnancy testing if the patient is of reproductive capacity. Then, CBC and LFTs should be tested Q2 weeks x 2 months, then monthly x 2 months, then as clinically indicated.
Any ongoing clinical trials related to abemaciclib?
Abemaciclib is being studied in the treatment of a large range of cancers such as pancreatic, head/neck, triple-negative breast cancer, glioblastoma, liposarcoma, and others. Find more info at http://clinicaltrials.gov.
LISA LOHR, PHARMD, BCOP, BCPS, is Clinical Oncology Specialist/MTM provider at Masonic Cancer Clinic Fairview/University of Minnesota Health, Minneapolis. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology and Director, Section of Medical Oncology, Washington University School of Medicine, St. Louis, Mo., serves as the Pharmacy Forum column physician advisor. SARA K. BUTLER, PHARMD, BCPS, BCOP, is Clinical Oncology Pharmacy Supervisor, Barnes-Jewish Hospital, St. Louis, Mo., and serves as a Pharmacy Forum column co-editor. JANELLE E. MANN, PHARMD, BCOP, is an Investigational Drug Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as the Pharmacy Forum column co-editor.