Abstract OT1-1-07: A phase III study of abemaciclib (LY2835219) combined with fulvestrant in women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer (MONARCH 2)
Authors: Llombart Antonio , Toi Masakazu , Klise Suzanne R , Frenzel Martin , Chan Edward M , Sledge George W 
Published: May 2015

Abstract
Background: Abemaciclib (LY2835219), an oral drug administered twice daily on a continuous schedule, is a cell cycle inhibitor of both CDK4 and CDK6. In Study I3Y-MC-JPBA, abemaciclib demonstrated evidence of single agent activity in a tumor-specific cohort of patients with metastatic breast cancer (MBC) and a median of 7 prior therapies; all responses observed were in women with HR+ disease. Abemaciclib also demonstrated an acceptable safety profile both as a single agent and in combination with fulvestrant. Based on these results, abemaciclib has been entered into a Phase III study (MONARCH 2) in combination with fulvestrant for women with locally advanced or metastatic hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer.
Trial design: MONARCH 2 (NCT02107703) is a randomized, double-blind, placebo-controlled Phase III study of fulvestrant with or without abemaciclib for women with HR+, HER2- locally advanced (not amenable to curative treatment by surgery) or metastatic breast cancer. Patients will be randomized 2:1 (Arm A [abemaciclib plus fulvestrant]: Arm B [placebo plus fulvestrant] with stratification based on the nature of disease (visceral metastases versus bone only metastases versus other) and sensitivity to endocrine therapy (no prior endocrine therapy versus primary resistance versus secondary resistance). Abemaciclib (200 mg every 12 hours [Q12H] on Days 1 to 28 of a 28-day cycle) or placebo will be given orally and fulvestrant 500 mg will be administered intramuscularly on Days 1 and 15 of Cycle 1, then on Day 1 of Cycle 2 and subsequent cycles.
Eligibility criteria: Postmenopausal women with HR+, HER2- inoperable locally advanced or metastatic breast cancer who have either relapsed after prior endocrine therapy or have not received prior endocrine therapy are eligible. Patients are required to have either measurable disease or non-measurable bone only disease, adequate organ function and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤1.
Specific aims: The primary objective of MONARCH 2 is to compare PFS between two treatment arms: abemaciclib plus fulvestrant versus placebo plus fulvestrant for women with HR+, HER2- locally advanced or metastatic breast cancer. Secondary objectives are to compare overall survival, objective response rate, clinical benefit rate, safety, pharmacokinetics and quality of life.
Statistical methods: The study has 90% power to detect an increase in PFS of approximately 42% (hazard ratio = .703). Assuming a median PFS of 6.5 mos. in the control arm, this corresponds to a 2.75 month increase in the median PFS to 9.25 mos. PFS and OS will be hierarchically tested to maintain an overall type I error rate of 2.5%.
Present accrual and target accrual: Target accrual is approximately 550 patients.
Contact information: For further information please contact 1-877-CTLILLY (1-877-285-4559).
Citation Format: Antonio Llombart, Masakazu Toi, Suzanne R Klise, Martin Frenzel, Edward M Chan, George W Sledge. A phase III study of abemaciclib (LY2835219) combined with fulvestrant in women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer (MONARCH 2) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-07.