Abstract P6-11-11: Abemaciclib exposure-response relationship in patients with metastatic breast cancer in MONARCH 1
Authors: O'Shaughnessy J , Chigutsa E , Kambhampati SRP , Sykes A , Frenzel M , Nanda S , Koustenis A , Smith I , Turner PK 
Published: March 2017

Abstract
Objective: Abemaciclib is an oral, selective inhibitor of CDK4 & 6 that exhibited single agent activity in the MONARCH 1 clinical trial1. The relationship between abemaciclib exposure as monotherapy and response for efficacy and adverse events was evaluated in patients with metastatic breast cancer.
Methods: Abemaciclib (200 mg) was administered orally on a continuous schedule every 12 hours in 28 day cycles until disease progression. Sparse pharmacokinetic samples (PK) were collected, cycle (C) 1 day (D) 1 pre dose, C1D15 4 and 7 hours post dose, C2D1 pre and 3 hours post dose, and pre dose on C3D1. Exposure metrics were predicted from a population PK model and included the minimum concentration after a single dose on D1(Cmin,d1), maximum concentration at steady state (Cmax,ss), and minimum concentration at steady state (Cmin,ss ). Exposure to abemaciclib, active metabolites LSN2839567 (M2) and LSN3106726 (M20), and total active species (abemaciclib + M2 + M20) were tested.
Response endpoints including efficacy and adverse events were evaluated 12 months after the last patient entered treatment. The relationship between exposure and objective response rate (ORR) was evaluated by quartile analysis and logistic regression. The relationship between exposure and progression free survival (PFS) was evaluated by Kaplan Meier analysis of exposure quartiles and a Cox Proportional Hazard model with PFS as the response and exposure as a covariate. The relationship between exposure and neutropenia, diarrhea, fatigue, nausea, vomiting, and any treatment emergent adverse event (TEAE) was evaluated by logistic regression on the incidence of any grade, grade≥ 2, and grade ≥ 3 events. No adjustments for multiplicity were performed.
Results: Analyses included 132 patients. A summary of the exposures in MONARCH 1 are presented in Table 1. The confirmed ORR was 19.7%, and median PFS was 5.95 months (95%CI: 4.2, 7.5). There was no statistically significant relationship between Cmin,d1, Cmin,ss, Cmax,ss for abemaciclib, M2, M20, or total analyte and ORR or PFS. There were no statistically significant and clinically relevant relationships between abemaciclib exposure and TEAEs.
Conclusion: The results of the exposure-response analysis support the abemaciclib single agent starting dose of 200 mg twice daily and dose reductions in 50 mg decrements as needed for adverse events. Further studies to refine the PK model and evaluate relationships between exposure and response are warranted.
Table 1 Abemaciclib exposures in MONARCH 1 Geometric Mean (µm) (CV%)AnalyteCmax,ss (µm)Cmin,d1 (µm)Cmin,ss (µm)Abemaciclib0.509 (42.6)0.136 (54.2)0.356 (59.9)M20.247 (62.4)0.0511 (51.4)0.187 (83.8)M200.395 (61)0.0687 (56.7)0.312 (79.9)Total Active Species1.19 (43.2)0.262 (47.6)0.888 (60.7)References: 1. Dickler, M. et al. American Society of Clinical Oncology (ASCO), abstract #510 (2016).
Citation Format: O'Shaughnessy J, Chigutsa E, Kambhampati SRP, Sykes A, Frenzel M, Nanda S, Koustenis A, Smith I, Turner PK. Abemaciclib exposure-response relationship in patients with metastatic breast cancer in MONARCH 1 [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 P6-11-11.