Abstract P6-15-01: Analysis of renal function in MONARCH 1: A phase 2 study of abemaciclib, a CDK4 & 6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for metastatic breast cancer (MBC)
Authors: Tolaney S , Lam AQ , Mukundan S , Nanda S , Cox J , Barriga S 
Published: May 2019

Abstract
Background: Abemaciclib is an oral, selective inhibitor of CDK4 & 6 that has demonstrated activity in different tumor types. In a phase 1 trial, treatment emergent adverse events (TEAEs) of increased creatinine, grade 1 or 2 severity by Common Terminology Criteria for Adverse Events (CTCAE v4.0) were reported in &gt; 10% of patients (pts) who received abemaciclib monotherapy1. In vitro, abemaciclib and its major metabolites inhibit renal transporters OCT2, MATE1, and MATE2-K2.
Methods: MONARCH 1 is a phase 2 single-arm study designed to evaluate safety and efficacy of abemaciclib monotherapy in women with HR+/HER2- MBC whose disease progressed on/after endocrine- and chemotherapy. Abemaciclib (200 mg) was administered orally on a continuous schedule every 12 hours until disease progression or unacceptable toxicity occurred. We retrospectively analyzed changes in serum creatinine, blood urea nitrogen (BUN), cystatin C, and calculated glomerular filtration rate (GFR) based on cystatin C using central lab values. TEAEs (CTCAE v4.0), dose delays, and treatment discontinuation associated with renal events were examined.
Results: Of the 132 pts treated, 130 pts had central laboratory data available, and 128 pts (98.5%) experienced an increased serum creatinine: 61 pts (46.9%) grade 1, 66 pts (50.8%) grade 2, 1 pt (0.8%) grade 3. Creatinine increases occurred during cycle 1 and remained elevated but stable during treatment. Serum creatinine decreased following treatment discontinuation. No changes in mean BUN, cystatin C or estimated GFR were observed.
TEAEs of increased serum creatinine were reported in 17 pts (12.9%); one was grade 3. Due to increased serum creatinine, 2 pts experienced dose reductions, 2 pts dose omissions, and 1 pt treatment discontinuation. Serious AEs (SAEs) of increased creatinine was were experienced by 4 patients; 3 were possibly related to abemaciclib. A non-drug related SAE of acute kidney injury was reported for 1 pt. Review of all reported AEs/SAEs failed to indicate any evidence of renal impairment.
The Standardized MedDRA Queries (SMQ) acute renal failure was used to search and identify all reported cases of increased creatinine with or without acute kidney injury. Twenty pts (15.2%) who experienced an AE were included in this category: 4 pts (3.0%) met the narrow term SMQ, and 17 pts (12.9%) the broad term SMQ.
Conclusions: Safety data from the MONARCH 1 study shows a causal association of the reversible increased blood creatinine with abemaciclib therapy, but not as a result of renal injury, renal insufficiency, or impaired renal function. The rise in serum creatinine is consistent with in vitro data indicating that abemaciclib is a competitive inhibitor of renal efflux transporters of creatinine2.
References:
1. Patnaik, Amita, et al. Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non–Small Cell Lung Cancer, and Other Solid Tumors. Cancer Discovery (2016).
2. Kulanthaivel, P. et al. Pharmacokinetic Drug Interactions Between Abemaciclib and CYP3A Inducers and Inhibitors. American Association for Cancer Research - 107th Annual Meeting, abstract #CT153 (2016).
Citation Format: Tolaney S, Lam AQ, Mukundan S, Nanda S, Cox J, Barriga S. Analysis of renal function in MONARCH 1: A phase 2 study of abemaciclib, a CDK4 & 6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for metastatic breast cancer (MBC) [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 P6-15-01.