Pharmacodynamics of GDC-0879, a Potent and Selective B-Raf Kinase Inhibitor: Understanding Relationships between Systemic Concentrations, pMEK1 Inhibition, and Efficacy

ABSTRACT The Raf/MEK/ERK signaling pathway is involved in cellular responses relevant to tumorigenesis, including cell proliferation, invasion, survival and angiogenesis. GDC-0879 is a novel, potent and selective B-Raf inhibitor. The objective of this study was to characterize the relationship between GDC-0879 plasma concentrations and tumor growth inhibition in A375 melanoma and Colo205 colon cancer xenografts, and to understand the pharmacodynamic (PD) marker response requirements (pMEK1 inhibition) associated with tumor growth inhibition in A375 xenografts. Estimates of GDC-0879 plasma concentrations required for tumor stasis obtained from fitting tumor data to indirect response models were comparable, at 4.48 and 3.27 µM for A375 and Colo205 xenografts, respectively. This was consistent with comparable in vitro potency of GDC-0879 in both cell lines. The relationship between GDC-0879 plasma concentrations and pMEK1 inhibition in the tumor was characterized in A375 xenografts following oral doses of 35, 50 and 100 mg/kg. Fitting pMEK1 inhibition to an indirect response model provided an IC