By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved a new targeted, oral treatment option for patients with breast cancer who are not responding to or who have not progressed following endocrine treatment. Abemaciclib is the third cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor (after palbociclib and ribociclib). Theses kinases are involved in cell cycle transition and cell division. Abemaciclib was designated as breakthrough therapy and given a priority review. Abemaciclib is marketed as Verzenio.
Abemaciclib is indicated in combination with fulvestrant for the treatment of women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer with disease progression following endocrine therapy.1 It is also indicated as monotherapy for the treatment of adults with HR+, HER2-, advanced, or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.
The recommended dose is 150 mg twice daily with fulvestrant or 200 mg twice daily as monotherapy.1 Dosage interruption and/or modification is based on severity of adverse events such as hematologic conditions, diarrhea, hepatotoxicity, and other toxicities.1 Abemaciclib is available as 50 mg, 100 mg, 150 mg, and 200 mg tablets.
Abemaciclib differs chemically compared to previous CDK4/6 inhibitors and is much more selective for CDK4 than CDK6.2,3 Cytopenia is less likely, thus allowing for continuous therapy compared to 21 days on and seven days off for palbociclib and ribociclib. It is the first CDK4/6 inhibitor approved for monotherapy.
Most frequent (> 30%) adverse reactions reported were diarrhea (86%), neutropenia (46%), nausea (45%), infections (43%), elevation of liver enzymes (37-41%), and abdominal pain (35%). Venous thromboembolic events were reported in 5% of patients, and there is potential for embryo-fetal toxicity. Fatigue and gastrointestinal toxicity is more common with abemaciclib compared to other CDK4/6 inhibitors.5 Strong CYP3A4 inhibitors may increase the toxicity of abemacicib.1
The approval of abemaciclib was based on two clinical trials. One was a single-arm, open-label study, and the other a randomized, double-blind study with fulvestrant, an estrogen receptor antagonist.1,4,5 The first study enrolled women with HR+ and HER2- metastatic breast cancer who had progressed on or after prior endocrine therapy, had received a taxane, and had received one or two chemotherapy regimens in the metastatic setting. Subjects (n= 132) were given abemaciclib (200 mg) every 12 hours until disease progression or unacceptable toxicity. Dose reduction and delay were allowed based on study protocol. The primary endpoint was investigator-assessed objective response rate (ORR). ORR was 19.7%, with a median duration of response of 8.6 months. This compares favorably to a historical response of 15% for chemotherapy.4
The authors of the second study examined subjects with HR+ and HER2- metastatic breast cancer who demonstrated disease progression following endocrine therapy who had not received chemotherapy in the metastatic setting.1,5 Subjects were randomized to abemaciclib (150 mg every 12 hours) + fulvestrant (500 mg intramuscularly on days 1 and 15 of cycle 1 and on day 1 of every 28-day cycle thereafter) or placebo + fulvestrant. Results were assessed based on 446 subjects on abemaciclib and 223 on placebo. Efficacy endpoints were progression-free survival (PFS) and objective tumor response rate (OTR) in subjects with measurable disease. PFS was 16.4 months for abemaciclib vs. 9.3 months for placebo (hazard ratio, 0.55; 95% confidence interval, 0.45-0.68). OTR based on 318 subjects on abemaciclib and 164 on placebo was 48% vs. 21%. In another Phase III study, abemaciclib was evaluated as initial therapy and has been reported to improve PFS and OTR compared to placebo when added to anastrozole or letrozole (aromatase inhibitors).6
More than 70% of patients with metastatic breast cancer are HR+ and treated with endocrine therapy.7 Over time, endocrine resistance can develop. Deregulation of CDK4/6 appears to play a role in breast cancer tumorigenesis and development of endocrine resistance.2 Current Cancer Comprehensive Network guidelines list palbociclib and ribociclib with an aromatase inhibitor as category 1 treatment for HR+ and HER2- postmenopausal patients with recurrent or stage IV disease and no prior endocrine therapy within one year (initial therapy).8 Abemaciclib plus fulvestrant is listed as an option for progression on prior endocrine therapy. There are no data to support trying another CDK4/6 regimen if there is disease progression.8 Abemaciclib monotherapy is indicated after progression on prior endocrine therapy and prior chemotherapy in the metastatic setting. Currently, it has not been approved for initial therapy.
- Verzenio Prescribing Information. Eli Lilly and Company. September 2017.
- Bilgin B, Sendur MAN, Şener Dede D, et al. A current and comprehensive review of cyclin-dependent kinase inhibitors for the treatment of metastatic breast cancer. Curr Med Res Opin 2017;33:1559-1569.
- 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. Oncologist 2017;22:1039-1048.
- Dickler MN, Tolaney SM, Rugo HS, 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 2017;23:5218-5224.
- Sledge GW Jr, Toi M, Neven P, 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 2017;35:2875-2884.
- Goetz MP, Toi M, Campone M, et al. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol 2017;35:3638-3646.
- U.S. Food and Drug Administration. FDA approves new treatment for certain advanced or metastatic breast cancers, Sept. 28, 2017. Available at: . Accessed Dec. 5, 2017.
- National Comprehensive Cancer Network. NCCN Guidelines. Available at: . Accessed Dec. 5, 2017.