Abstract P257: Preclinical data identifies bezuclastinib as a differentiated KIT inhibitor with unique selectivity to KIT D816V and minimal evidence of brain penetration
Authors: Guarnieri Anna , Chicarelli Mark , Cable LouAnn , Sullivan Francis , Ball Howard , Winski Shannon , Robinson John 
Published: December 2021

Abstract
KIT is a well characterized oncogenic driver of gastro-intestinal stromal tumors (GIST) and systemic mastocytosis (SM), and targeted therapeutics have offered valuable treatment options for these patients. Durable responses in imatinib-resistant GIST are rarely achieved due to secondary mutations that occur in exons 13/14 and 17/18. Exon 13/14 mutations can be addressed with sunitinib treatment, but identifying inhibitors that additionally target exon 17/18 mutations without incurring off-target toxicities related to broad-spectrum kinase inhibition has been challenging. Similarly, agents targeting KIT D816V mutations have shown activity in the treatment of advanced SM, but toxicities such as cognitive effects and intracranial hemorrhage may limit dosing and availability of these therapies. Bezuclastinib (CGT9486) was designed to inhibit exon 17/18 KIT mutations (including KIT D816V) with selectivity versus other closely-related kinases with known liabilities, such as PDGFRα, PDGFRβ, KIT wt, VEGFR2 (KDR), and CSF1R (FMS). Herein, we are presenting results from cell-based kinase profiling assays, which demonstrate that bezuclastinib has a significant and unique selectivity to KIT D816V vs. these aforementioned kinases when tested head-to-head against other clinically relevant compounds in GIST or SM. Additionally, a similar selectivity profile was observed for a broader panel of kinases, ion channels, transporters, and enzymes, which will be presented here. Importantly, we also show that bezuclastinib has minimal brain penetration. In a tissue distribution study performed in rats, bezuclastinib shows a brain:plasma ratio &lt;0.1 following 3 day administration at 25 mg/kg, a dose that closely correlates with clinical exposure. This was supported functionally by assessing neurobehavioral effects of bezuclastinib at dose levels up to 100 mg/kg which showed no CNS related effects. Minimal brain penetration is a preferred feature of an anti-Kit molecule due to CNS-related adverse events observed in these indications. This attractive selectivity and nonclinical safety profile, combined with early clinical data (1) in advanced solid tumors, supports the potential for a best-in-class KIT inhibitor. Bezuclastinib is currently under clinical investigation in advanced SM with additional clinical studies planned in non-advanced SM and imatinib-resistant GIST. 1. Jonathan Trent, William D. Tap, Rashmi Chugh, Gabriel Tinoco, Athanasios Tsiatis, Paul Severson, Kerry Inokuchi, Chao Zhang, Glenn Michelson, Andrew J. Wagner. The Potent and Selective KIT Inhibitor PLX9486 Dosed in Combination With Sunitinib Demonstrates Promising Progression Free Survival (PFS) in Patients With Advanced Gastrointestinal Stromal Tumor (GIST): Final Results of a Phase 1/2 Study. Abstract Presented at the Connective Tissue Oncology Society Virtual Meeting; November 20, 2020.
Citation Format: Anna Guarnieri, Mark Chicarelli, LouAnn Cable, Francis Sullivan, Howard Ball, Shannon Winski, John Robinson. Preclinical data identifies bezuclastinib as a differentiated KIT inhibitor with unique selectivity to KIT D816V and minimal evidence of brain penetration [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P257.