Window of opportunity study measuring defactinib and avutometinib delivery in glioblastomas.

purposeGlioblastoma (GBM) is the most common malignant brain tumor in adults, and durable control or cure with current standard or investigational therapies is rare. Therefore, novel approaches are needed. This exploratory study evaluated whether defactinib and avutometinib, inhibitors of FAK/Pyk2 and RAF/MEK signaling respectively, penetrate GBM and produce measurable effects on their molecular targets.

methodsDefactinib or avutometinib was administered to six subjects each, in two escalating dose levels: avutometinib at 3.2 mg and 4 mg, and defactinib at 200 mg and 400 mg (three patients per dose level). Administration occurred immediately prior to craniotomy for tumor resection. Tumor tissue, peritumoral brain tissue, and blood were collected during surgery. Drug concentrations were measured by liquid chromatography-mass spectrometry, and effects on the intended molecular targets were assessed by western blot analysis.

resultsEven after a single preoperative dose, both defactinib and, to a lesser extent, avutometinib were detectable in tumor tissue 3-4 h after administration. Peritumoral brain tissue contained lower concentrations of each agent. Exploratory pharmacodynamic analyses suggested target engagement: avutometinib (3.2 mg) reduced Erk1/2 phosphorylation approximately 28-fold, while defactinib (400 mg) reduced Pyk2 phosphorylation by 5.7-fold within tumor tissue. Effects in peritumoral tissue were minimal.

conclusionThese exploratory findings demonstrate that defactinib and avutometinib can penetrate GBM tissue and produce measurable modulation of their intended molecular targets after a single dose, with limited impact on surrounding brain. While the small sample size and inherent tissue heterogeneity limit definitive conclusions, this study supports the feasibility of presurgical pharmacokinetic and pharmacodynamic evaluation in GBM and provides a rationale for further clinical studies to optimize dosing, target inhibition, and therapeutic efficacy. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT05798507. Date of Registration March 3, 2023.