Abstract 6296: Preclinical evaluation of a panel of FGFR inhibitors for their normal brain and brain tumor distribution

Abstract Glioblastoma (GBM) is the most prevalent and lethal primary intrinsic brain tumor in adults with approximately 5-8% of GBM patients displaying fibroblast growth factor receptor (FGFR) gene mutations. This subset of GBM patients could potentially benefit from targeted FGFR inhibitor treatment, thus making it imperative to explore FGFR inhibitors as a therapeutic option. In this study, seven pan-FGFR inhibitors (infigratinib, AZD4547, debio1347, erdafitinib, LY2874455, pemigatinib, and TAS-120) were evaluated for their brain penetration ability employing cassette dosing strategy with an aim to identify the optimal candidates for brain tumor targeting. Cassette-dosing strategy was confirmed to be an acceptable approach for screening the panel of FGFR inhibitors by comparing pharmacokinetic parameters obtained from discrete- vs cassette-dosing studies. Subsequently, cassette-dosing strategy was utilized to investigate distributional kinetics of FGFR inhibitors in normal brain and brain tumor in wild-type and triple-knockout (Mdr1a/b-/-Bcrp1-/-) mice. The comparison of brain-to-plasma partition coefficients for total (Kp,brain) and unbound (Kp,brain) drug levels in wild-type and triple-knockout mice revealed the importance of major blood-brain barrier (BBB) efflux transporters in four out of seven FGFR inhibitors. The impact of BBB and efflux transporters were further evaluated in flank and orthotopic patient-derived xenograft mouse models of brain tumors. All FGFR inhibitors were shown to accumulate significantly in both flank and orthotopic brain tumors relative to normal brain. Furthermore, the levels in flank brain tumors were at least 10-fold higher as compared to the levels in orthotopic brain tumors with five FGFR inhibitors, indicating the critical role of efflux transporters and the impact of BBB disruption in the brain and brain tumor distribution. The predictive parameters of brain penetration calculated based on physico-chemical properties have been estimated and shown not to correlate with the experimentally obtained neuro-pharmacokinetic values. In summary, our study provides comprehensive evaluation of neuro-pharmacokinetic behavior of seven FGFR inhibitors and delivers rationale for selection of most optimal candidates for future investigation in brain tumor clinical trials. Citation Format: William Knight, Kamal Shaik, Tigran Margaryan, Shwetal Mehta, Nader Sanai, Artak Tovmasyan. Preclinical evaluation of a panel of FGFR inhibitors for their normal brain and brain tumor distribution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6296.