Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Xenograft

Effective treatments for primary brain tumors and brain metastases represent a major unmet medical need. Targeting the CDK4/6-cyclin D1-Rb-p16/ink4a pathway using a potent CDK4 and CDK6 kinase inhibitor has potential for treating primary CNS tumors such as glioblastoma and some peripheral tumors with high incidence of brain metastases. We compared CNS exposures of two orally bioavailable CDK4 and CDK6 inhibitors: abemaciclib that is currently in advanced clinical development and palbociclib (IBRANCE®, Pfizer), which was recently approved by the U.S. Food and Drug Administration. Abemaciclib antitumor activity was assessed in subcutaneous and orthotopic glioma models alone and in combination with standard of care temozolomide (TMZ). Both inhibitors were substrates for xenobiotic efflux transporters P-glycoprotein and breast cancer resistant protein expressed at the blood-brain barrier (BBB). Brain Kp,uu values were less than 0.2 after equimolar intravenous dose indicative of active efflux, but were ~10 fold greater for abemaciclib than palbociclib. Kp,uu increased 2.8 and 21 fold, respectively, when similarly dosed in P-gp-deficient mice. Abemaciclib had a brain AUC(0-24 h) Kp,uu of 0.03 in mice and 0.11 in rats following a 30 mg/kg PO dose. Orally-dosed abemaciclib significantly increased survival in a rat orthotopic U87MG xenograft model compared to vehicle-treated animals and efficacy coincided with a dose-dependent increase in unbound plasma and brain exposures in excess of the CDK4 and CDK6 Ki values. Abemaciclib increased survival time of intracranial U87MG tumor-bearing rats similar to TMZ and the combination of abemaciclib and TMZ was additive or greater than additive. These data show abemaciclib crosses the BBB and confirm that both CDK4 and CDK6 inhibitors reach unbound brain levels in rodents that are expected to produce enzyme inhibition, but abemaciclib brain levels are reached more efficiently at presumably lower doses than palbociclib and are potentially on target for a longer period of time.