Abemaciclib Receives FDA Approval for Some Women with Breast Cancer

On September 28, 2017, following an expedited Priority Review, the FDA approved abemaciclib (Verzenio) for the treatment of certain patients with advanced or metastatic breast cancer.¹ Abemaciclib is the first and only CDK4/6 inhibitor that is FDA approved for use in combination with fulvestrant and as monotherapy.²

In a recent press release by Lilly,² Marc Hurlbert, PhD, Chairman of the Metastatic Breast Cancer Alliance, stated, “The approval of Verzenio marks an exciting day for the metastatic breast cancer community. For women living with advanced disease, every new treatment approved offers the hope of possibility—that their oncologists have more options that may help slow the spread of this deadly cancer.”

Abemaciclib is the only CDK4/6 inhibitor that can be dosed continuously with no interruption in treatment,³ unlike ribociclib⁴ and palbociclib,⁵ which need to be stopped for 7 days after 21 days of therapy because of hematologic toxicity.
The indications for abemaciclib are as follows³:

• In combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy
• As monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.

FDA approval was based on safety and efficacy results from 2 pivotal trials. In the MONARCH 1 trial, abemaciclib was evaluated as monotherapy in patients with HR-positive, HER2-negative metastatic breast cancer who had received prior endocrine therapy and 1 to 2 chemotherapy regimens in the metastatic setting.6 MONARCH 1 was a single-arm, phase 2 trial in which 132 patients received abemaciclib 200 mg orally twice daily until the development of progressive disease or unmanageable toxicity. Patients in the trial were quite ill, with 90% having visceral metastases and 51% having ≥3 sites of metastatic disease. Efficacy in the intent-to-treat population was assessed by the investigator and by an independent review. The investigator-assessed objective response rate (ORR) was 19.7%, and the independent review ORR was 17.4%. The investigator-assessed median duration of response was 8.6 months, and the independent review median duration of response was 7.2 months.⁶

In the MONARCH 2 trial, abemaciclib was evaluated in combination with fulvestrant in patients with HR-positive, HER2-negative metastatic breast cancer with disease progression on or after prior adjuvant or metastatic endocrine therapy.⁷ MONARCH 2 was a randomized, double-blind, placebo-controlled phase 3 study of 669 patients who were randomized to abemaciclib or placebo orally twice daily plus intramuscular injection of fulvestrant 500 mg on days 1 and 15 of cycle 1 and then on day 1 of cycle 2 and beyond (28-day cycles). Patients received continuous treatment until development of progressive disease or unmanageable toxicity. Among the patients in the trial, 20% had de novo metastatic disease, 27% had bone-only disease, and 56% had visceral disease. Among the intent-to-treat population, 49.8% of patients receiving abemaciclib plus fulvestrant and 70.4% receiving placebo plus fulvestrant had a progressive event (P <.0001).

Patients in the abemaciclib plus fulvestrant arm had a 16.4-month median progression-free survival (PFS) versus 9.3 months for those in the placebo plus fulvestrant arm. The ORR for patients with measurable disease was 48.1% with abemaciclib plus fulvestrant compared with 21.3% with placebo plus fulvestrant.^2,7

The MONARCH 3 trial evaluated abemaciclib as first-line therapy in patients with advanced breast cancer. Results from this trial were recently published in the Journal of Clinical Oncology.⁸ MONARCH 3 was a double-blind, randomized phase 3 study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Results showed that treatment with abemaciclib significantly improved median PFS. In addition, in patients with measurable disease, the ORR was 59% with abemaciclib versus 44% with placebo, which was statistically significant.

The most common treatment-emergent adverse events that occurred in ≥20% of patients treated with abemaciclib in clinical trials were diarrhea, neutropenia, nausea, abdominal pain, infection, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, and thrombocytopenia. Discontinuations due to adverse events were infrequent (<10%) in the MONARCH 1, 2, and 3 trials.^6-8

References
1. US Food & Drug Administration. FDA approves new treatment for certain advanced or metastatic breast cancers. Press release. September 28, 2017. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm578071.htm. Accessed November 20, 2017.
2. Eli Lilly and Company. Lilly receives U.S. FDA approval of Verzenio™ (abemaciclib). Press release. October 4, 2017. https://investor.lilly.com/releasedetail.cfm?ReleaseID=1042898. Accessed November 20, 2017.
3. Verzenio (abemaciclib) tablet [prescribing information]. Indianapolis, IN: Eli Lilly and Company; September 2017.
4. Kisqali (ribociclib) tablets, for oral use [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; March 2017.
5. Ibrance (palbociclib) capsules, for oral use [prescribing information]. New York, NY: Pfizer Labs; March 2017.
6. 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.
7. 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.
8. 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.