Background:

Abemaciclib is a potent oral CDK4 and 6 inhibitor, which demonstrated evidence of clinical activity and an acceptable safety profile on a continuous dosing schedule either as a single agent (MONARCH 1; NCT02102490) or in combination with endocrine therapies in heavily pre-treated women with HR+ metastatic breast cancer (BC).1,2

Methods:

neoMONARCH (NCT02441946) is a randomized, multicenter, open-label phase 2 neoadjuvant study comparing the biological effects of abemaciclib plus anastrozole vs abemaciclib monotherapy vs anastrozole monotherapy in women with early-stage HR+, HER2- BC. Patients (pts) were stratified by progesterone receptor status and tumor size and randomized 1:1:1 ([abemaciclib 150mg orally [PO] every 12 hours [Q12H] plus anastrozole 1 mg PO daily [QD]], [abemaciclib 150mg PO Q12H], and [anastrozole 1mg PO QD]). Each regimen was given for 2 weeks; followed by all pts receiving abemaciclib 150mg PO Q12H plus anastrozole 1mg QD for the subsequent 14 weeks. All pts received prophylactic loperamide during the first 28 days of abemaciclib therapy, then at the discretion of the investigator. Eligible pts included postmenopausal women with HR+, HER2- clinical Stage I breast tumor ≥1 cm in diameter, Stage II, Stage IIIA, or IIIB BC. The primary objective: compare biological activity by assessing the percent change from baseline value in Ki67 protein expression after 2 weeks of therapy with the three initial regimens. Clinical activity and safety of the subsequent 14 weeks of therapy of abemaciclib plus anastrozole are evaluated as secondary objectives at surgery. Exploratory objectives included assessment of changes in cell cycle mRNAs by Modaplex (QIAGEN) analyses and PIK3CA and ESR1 mutational analysis in core biopsy samples.

Statistical methods:

The design provides 80% power to detect superiority of the combination vs anastrozole monotherapy, and 80% power to detect superiority of abemaciclib monotherapy vs anastrozole monotherapy, at a 1-sided alpha level of 0.1. Secondary and exploratory objectives will be presented as descriptive data.

Results:

Enrollment of 223 pts began August 2015 and was completed August 2016. At a 9 month interim analysis, abemaciclib, given either as monotherapy or in combination with anastrozole showed significantly (p<0.001, n=64) greater suppression of Ki67 after 14 days of dosing than anastrozole alone. The safety profile of the combination differed from that previously reported for abemaciclib 200mg BID monotherapy in the MONARCH 1 study1 and the Phase Ib2 with reduced incidence of diarrhea and hematologic events. Change in proliferation gene mRNAs after 2 weeks of treatment (n=38), in both tumor and blood, appeared to correlate with change in Ki67 expression, with a greater reduction in the abemaciclib-containing arms. Updated data will be presented including safety data for all 223 pts, molecular data on approximately 150 pts who are evaluable for change in Ki67 and mRNA expression at 2 weeks and approximately 100 pts evaluable for clinical efficacy, final Ki67 and RNA expression at surgery.

References:

1. Dickler, M.et al., ASCO abstract #510 (2016).

2. Goetz, M.et al., SABCS abstract #P4-13-25 (2015).

Citation Format: Hurvitz S, Martin M, Fernández Abad M, Chan D, Rostorfer R, Petru E, Barriga S, Costigan TM, Caldwell CW, Nguyen T, Press M, Slamon D. Biological effects of abemaciclib in a phase 2 neoadjuvant study for postmenopausal patients with HR+, HER2- breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S4-06.