Early in 2018, abemaciclib (Verzenio) in combination with an aromatase inhibitor was approved as initial endocrine-based therapy for postmenopausal women with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer.1,2
Supporting Efficacy Data
Approval was based on findings in the double-blind phase III MONARCH 3 trial, in which 493 patients were randomized 2:1 to receive oral abemaciclib at 150 mg (n = 328) or placebo (n = 165) twice daily plus physician’s choice of the nonsteroidal aromatase inhibitors letrozole (80% of patients) or anastrozole (20% of patients).2,3 Randomization was stratified by disease site and by prior neoadjuvant endocrine therapy.
Abemaciclib carries warnings/precautions for diarrhea, neutropenia, hepatotoxicity, venous thromboembolism, and embryofetal toxicity.
Estimated median progression-free survival on Response Evaluation Criteria in Solid Tumors v1.1 was 28.2 months (95% confidence interval [CI] = 23.5 months to not reached) in the abemaciclib group vs 14.8 months (95% CI = 11.2–19.2 months) in the placebo group (hazard ratio = 0.540, P < .0001). Objective response rates in 267 abemaciclib patients and 132 placebo patients with measurable disease were 55.4% vs 40.2%.
How It Works
Abemaciclib is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). These kinases are activated upon binding to D cyclins. In estrogen receptor–positive breast cancer cell lines, cyclin D1 and CDK4/6 promote phosphorylation of the retinoblastoma protein (Rb), cell-cycle progression, and cell proliferation. In vitro, continuous exposure to abemaciclib inhibited Rb phosphorylation and blocked progression from G1 into S phase of the cell cycle, resulting in senescence and apoptosis. In breast cancer xenografts, abemaciclib dosed daily without interruption as a single agent or in combination with antiestrogens resulted in reductions in tumor size.
How It Is Used
The recommended starting dose of abemaciclib in combination with an aromatase inhibitor is 150 mg twice daily with or without food. Full prescribing information for the individual agents should be consulted for the recommended dose of the aromatase inhibitor being used. For patients with severe hepatic impairment, the abemaciclib dosing frequency should be reduced to once daily. Treatment should continue until disease progression or unacceptable toxicity.
Dose reductions for management of adverse events are stepwise to 100 and 50 mg twice daily for use in combination with an aromatase inhibitor. Treatment should be discontinued in patients unable to tolerate 50 mg twice daily. Specific guidelines are provided in the product labeling for dose modification for hematologic toxicities, diarrhea, hepatotoxicity, other persistent or recurrent toxicities. Treatment should be discontinued for an elevation in aspartate transaminase (AST) or alanine transaminase (ALT) > 3 times the upper limit of normal (ULN) plus total bilirubin > 2 times ULN in the absence of cholestasis and for grade 4 AST/ALT elevation (> 20.0 times ULN).
Complete blood cell counts must be monitored prior to the start of treatment, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. At the first sign of loose stools, treatment with antidiarrheal agents should be started and intake of oral fluids increased. ALT, AST, and serum bilirubin levels should be monitored prior to the start of treatment, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated.
Concomitant use of the strong CYP3A inhibitor ketoconazole should be avoided. For concomitant use of other strong CYP3A inhibitors (eg, itraconazole, clarithromycin), starting doses of abemaciclib of 200 mg twice daily or 150 mg twice daily should be reduced to 100 mg twice daily, and patients who have had a dose reduction to 100 mg twice daily due to adverse reactions should have a further reduction to 50 mg twice daily. If the strong CYP3A inhibitor is discontinued, the abemaciclib dose can be increased to the dose used prior to starting the strong inhibitor after 3 to 5 half-lives of the inhibitor. Concomitant use of strong CYP3A inducers (eg, rifampin, phenytoin, carbamazepine) should be avoided.
The most common adverse events of any grade occurring in at least 20% of patients receiving abemaciclib in MONARCH 3 and with > 2% higher frequency vs the placebo group were diarrhea (81% vs 30%), neutropenia (41% vs 2%), fatigue (40% vs 32%), infections (39% vs 2%), nausea (39% vs 20%), abdominal pain (29% vs 12%) , anemia (28% vs 5%), vomiting (28% vs 12%), alopecia (27% vs 11%), decreased appetite (24% vs 9%), and leukopenia (21% vs 2%). The most common grade 3 or 4 adverse events in the abemaciclib group included neutropenia, diarrhea, leukopenia, anemia, and increased ALT.
Adverse events led to dose reduction in 43% of the abemaciclib group, with the most common causes being diarrhea and neutropenia. The incidence of diarrhea was greatest during the first month of treatment; the median time to onset of diarrhea was 8 days, and the median durations of diarrhea for grade 2 and for grade 3 were 11 and 8 days. Most diarrhea events recovered or resolved (88%) with supportive treatment or dose reduction. Adverse events led to treatment discontinuation in 13% of patients (vs 3% of the placebo group). Death during treatment or 30-day follow-up occurred in 11 patients in the abemaciclib group vs 3 patients in the placebo group. Causes of death in abemaciclib patients were underlying disease, lung infection, venous thromboembolic event, pneumonitis, and cerebral infarction.
Abemaciclib carries warnings/precautions for diarrhea, neutropenia, hepatotoxicity, venous thromboembolism, and embryofetal toxicity. Women taking abemaciclib should not breastfeed. ■
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
1. U.S. Food and Drug Administration: FDA approves abemaciclib as initial therapy for HR-positive, HER2-negative metastatic breast cancer. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm598404.htm. Accessed July 23, 2018.
2. Verzenio (abemaciclib) tablets prescribing information, Eli Lilly and Company, February 2018. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208855s000lbl.pdf. Accessed July 23, 2018.
3. Goetz MP, Toi M, Campone M, et al: MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol 35:3638-3646, 2017.