Abstract 147: Bezuclastinib is a differentiated KIT inhibitor that exhibits unique selectivity to KIT A-loop mutations, minimal brain penetration, and favorable pharmacokinetic properties in preclinical models
Authors: Guarnieri Anna , Bouhana Karyn , Cable LouAnn , Rieger Rob , Haygood Leyla , Robinson John , Winski Shannon 
Published: June 2022

Abstract
KIT is a well characterized oncogenic driver, mutated in up to 80% of gastro-intestinal stromal tumors (GIST). Front-line imatinib is effective in many patients but durable responses in the setting of imatinib failure are rarely achieved due to complex secondary mutations that arise in the KIT ATP-binding pocket (exons 13/14) or the activation (A)loop (exons 17/18). Second-line sunitinib is active against exon 13/14 mutations but not A-loop mutations and identifying inhibitors that target the spectrum of possible mutations without incurring off-target toxicities related to broad-spectrum kinase inhibition has been challenging. Bezuclastinib (CGT9486) is a novel type I tyrosine kinase inhibitor that was designed as a potent and selective inhibitor of KIT A-loop mutations to address this unmet medical need. Herein, we present nonclinical data on the differentiated selectivity profile of bezuclastinib compared with other KIT inhibitors. We show that bezuclastinib is a low nanomolar inhibitor of KIT A-loop mutants which uniquely avoids targeting closely related kinases with known liabilities (e.g., PDGFRA, PDGFRB, CSF1R, and KDR) versus other approved inhibitors. In vivo pharmacokinetic/pharmacodynamic (PKPD) relationships have been evaluated utilizing either HMC1.2 human mast cell leukemia tumors for KIT phosphorylation or a Ba/F3-KIT-D816V splenomegaly model. In these models, plasma exposure associated with 50% reduction in splenomegaly or KIT phosphorylation was observed at 3-10 mg/kg/day corresponding to exposures 1.5-2.2 µg∙hr/mL. This correlated well with plasma exposure required to cause significant tumor growth inhibition in a GIST patient-derived xenograft model harboring an A-loop mutation (~1.3 µg∙hr/mL). Maximal efficacy in the PKPD models and tumor regression in GIST disease models was observed in exposure ranges of 19-36 or 11-44 µg∙hr/mL, respectively, which corresponds to clinically reached exposures in a recent GIST combination study of bezuclastinib with sunitinib. Importantly, in nonclinical studies, we also show that bezuclastinib has minimal brain penetration, a preferred feature of an anti-KIT molecule due to CNS-related adverse events observed in this targeted class. We present a tissue distribution study which demonstrates a brain:plasma ratio &lt;0.1 following a 3-day administration at a dose that correlates with clinical exposure. This attractive selectivity and nonclinical safety profile, combined with early clinical data in advanced solid tumors, supports the potential for a best-in-class KIT inhibitor. Bezuclastinib is currently under clinical investigation in advanced SM (Phase 2, Apex NCT04996875), non-advanced SM (Phase 2, Summit), and imatinib-resistant GIST (Phase 3, Peak).
Citation Format: Anna Guarnieri, Karyn Bouhana, LouAnn Cable, Rob Rieger, Leyla Haygood, John Robinson, Shannon Winski. Bezuclastinib is a differentiated KIT inhibitor that exhibits unique selectivity to KIT A-loop mutations, minimal brain penetration, and favorable pharmacokinetic properties in preclinical models [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 147.