On September 28, 2017, the cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor abemaciclib (Verzenio) was approved for use in combination with fulvestrant (Faslodex) for women with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. Abemaciclib was also approved as monotherapy for women and men with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.^1,2

Supporting Efficacy Data

The approval in combination with fulvestrant was based on findings in the phase III MONARCH 2 trial, in which 669 women who had not received chemotherapy for metastatic disease were randomized to receive either abemaciclib at 150 mg twice daily (n = 446) or placebo (n = 223) plus intramuscular (IM) fulvestrant at 500 mg on days 1 and 15 of cycle 1 and then on day 1 of cycle 2 and beyond in 28-day cycles.^2,3 Patients remained on continuous treatment with abemaciclib until development of progressive disease or unmanageable toxicity.

Median progression-free survival was 16.4 months in the abemaciclib group vs 9.3 months in the placebo group (hazard ratio [HR] = 0.553, P < .0001). Objective response rates among patients with measurable disease were 48.1% vs 21.3%, respectively.

Approval as monotherapy was based on findings in the phase II MONARCH 1 study, in which 132 women who had received a taxane in any setting and had received one or two prior chemotherapy regimens in the metastatic setting were treated with abemaciclib at 200 mg orally twice daily on a continuous schedule until progressive disease or unmanageable toxicity.^2,4 The objective response rate was 19.7% (95% confidence interval = 13.3%–27.5%), with a median response duration of 8.6 months.

How It Works

Abemaciclib is a CDK4/6 inhibitor. 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 reduction of the tumor size.

How It Is Used

When used in combination with fulvestrant, the recommended dose of abemaciclib is 150 mg orally twice daily. When given with abemaciclib, the recommended dose of fulvestrant is 500 mg on days 1, 15, and 29 and once monthly thereafter. Pre/ perimenopausal women receiving the combination of abemaciclib plus fulvestrant should be treated with a gonadotropin-releasing hormone agonist according to current clinical practice standards. When used as monotherapy, the recommended dose of abemaciclib is 200 mg orally twice daily. For patients with severe hepatic impairment (Child Pugh class C disease), the dosing frequency must 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 in combination use and to 150, 100, and 50 mg twice daily for use as monotherapy. 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 grade 2 toxicities as well as grade 3 or 4 toxicities. Treatment should be discontinued without suspending or lowering the dose for 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 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 abemaciclib with other strong CYP3A inhibitors (eg, itraconazole, clarithromycin), the starting dose 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 concomitant treatment after three to five half-lives of the CYP3A inhibitor. Concomitant use of strong CYP3A inducers (eg, rifampin) should be avoided.

Safety Profile

In THE MONARCH 2 trial, the most common adverse events of any grade (≥ 20%) in the abemaciclib plus fulvestrant group were diarrhea (86% vs 25% in placebo plus fulvestrant group), fatigue (46% vs 32%), neutropenia (46% vs 4%), nausea (45% vs 23%), infections (43% vs 25%), abdominal pain, anemia, leukopenia, decreased appetite, vomiting, and headache. The most common grade 3 or 4 adverse events (≥ 5%) were neutropenia (27% vs 1%), diarrhea (13% vs < 1%), leukopenia, anemia, and infections.

Adverse events led to dose reductions in 43% of the abemaciclib group, including due to diarrhea in 19% and neutropenia in 10%. Adverse events led to treatment discontinuation in 9% vs 3% of patients, with the most common causes in the abemaciclib group being infection (2%), diarrhea (1%), and hepatotoxicity (1%). Deaths during treatment or 30-day follow up occurred in 18 patients in the abemaciclib group, including due to underlying disease in 7, sepsis in 4 (0.9%), pneumonitis in 2 (0.5%), hepatotoxicity in 2 (0.5%), and cerebral infarction in 1.

In MONARCH 1 trial, the most common adverse events of any grade (≥ 20%) with abemaciclib monotherapy were diarrhea, fatigue, nausea, decreased appetite, abdominal pain, neutropenia, vomiting, infections, anemia, headache, and thrombocytopenia. The most common grade 3 or 4 adverse events (≥ 5%) were diarrhea (20%), neutropenia (19%), fatigue (13%), infections, nausea, anemia, and leukopenia. Adverse events led to dose reduction in 49% of patients and treatment discontinuation in 8%. Deaths during treatment or 30-day follow up were reported in 2% of patients, with all deaths due to infection.

Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters, without affecting glomerular function.

Abemaciclib carries warnings/precautions for diarrhea, neutropenia, hepatotoxicity, venous thromboembolism, and embryofetal toxicity. Women taking abemaciclib should not breastfeed. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves abemaciclib for HR-positive, HER2-negative breast cancer. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm578081.htm. Accessed November 7, 2017.

2. Verzenio (abemaciclib) prescribing information, Eli Lilly, September 2017. Available at www.accessdata.fda.gov. Accessed November 7, 2017.

3. Sledge GW Jr, et al: MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2– advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol 35:2875-2884, 2017.

4. Dickler MN, et al: MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2– metastatic breast cancer. Clin Cancer Res 23:5218-5224, 2017.