Preliminary Safety and Efficacy from Apex, a Phase 2 Study of Bezuclastinib (CGT9486), a Novel, Highly Selective, Potent KIT D816V Tyrosine Kinase Inhibitor, in Adults with Advanced Systemic Mastocytosis (AdvSM)

Background: Systemic mastocytosis (SM) is a rare disease characterized by the proliferation of mast cells (MC). In about 95% of adult patients, SM is driven by a gain-of-function mutation (D816V) in exon 17 of the KIT gene. Advanced SM (AdvSM) is an aggressive, life-threatening form of SM and includes three subtypes; aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and MC leukemia (MCL). Bezuclastinib is an oral, highly selective, and potent tyrosine kinase inhibitor (TKI) with specificity for mutations in KIT exons 9, 11, 17, and 18, including D816V, while sparing closely related kinases (e.g., PDGFRα, PDGFRβ, and CSF1R). Results from a phase 1/2 study in patients with advanced solid tumors coupled with preclinical data have led to the on-going evaluation of bezuclastinib in patients with AdvSM, the Apex study (NCT04996875). The primary objective of this study is to evaluate the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) profile of bezuclastinib in all AdvSM subtypes.

Methods: Apex is a Phase 2, open-label, 2-part, multicenter study in adult patients with AdvSM per WHO diagnostic criteria, who have measurable SM-related organ damage according to modified IWG-MRT-ECNM consensus eligibility and response criteria (mIWG), and have a baseline serum tryptase of ≥20 ng/mL. Patients with a history of prior TKI therapy (e.g., avapritinib, midostaurin) are permitted in the study. In Part 1, patients are randomized 1:1:1:1 to bezuclastinib 50, 100, or 200 mg BID, or 400 mg QD. Data from Part 1 will inform dose selection for Part 2. The primary efficacy endpoint for this study is overall response rate (complete response [CR], CR with incomplete hematologic recovery [CRh], partial response [PR] and clinical improvement [CI]) as assessed by a Central Response Review Committee and based on mIWG response criteria.

Results: As of May 24, 2022, 11 mIWG evaluable patients with AdvSM (ASM: n=2, SM-AHN: n=8, and MCL: n=1) were randomized in Part 1 to 50mg BID (n=3), 100mg BID (n=3), 200mg BID (n=3), and 400mg QD (n=2). The majority of patients were male (82%) and treatment naïve (82%) with ECOG PS 0-1 (82%) and positive for KIT D816V (91%). Median (range) BM MC burden and serum tryptase at baseline were 30% (7-80%) and 182 ng/mL (68-1578 ng/mL), respectively. Bezuclastinib was well-tolerated across all dose levels. Treatment Emergent Adverse Events (TEAEs) reported in >1 patient included anemia (n=3), neutropenia (n=2), and thrombocytopenia (n=2), a majority of which were low-grade. One serious AE of hypersensitivity (mediator flare) was reported. Two patients had an AE-related dose reduction with one patient subsequently re-escalating to the randomized dose. Preliminary clinical activity data showed that all 11 patients experienced a >50% reduction in serum tryptase from baseline, 10/11 (91%) within the first week of treatment; 6 (55%) patients achieved a serum tryptase level <20 ng/mL, 4/6 within the first cycle of treatment. Among patients with available data after ≥2 cycles of treatment, all 8 achieved a median reduction of 68% in KIT D816V variant allele fraction (VAF) and ≥50% reduction in BM MC, with 6/8 (75%) achieving complete clearance of MC aggregates. There were no reported instances of cognitive effects or intracranial bleeding.

Conclusion: Early data suggest that bezuclastinib is well-tolerated and is associated with encouraging early signs of clinical activity as demonstrated by meaningful reductions in serum tryptase, MC burden, and KIT D816V VAF. Enrollment is currently ongoing. Updated safety and clinical activity as well as initial clinical objective response data will be presented.

DeAngelo:AbbVie, Blueprint Medicines Corporation, GlycoMimetics, and Novartis: Research Funding; AbbVie, Amgen, Autolus, Blueprint Medicines Corporation, Forty-Seven, GlycoMimetics, Incyte, Jazz, Kite, Novartis, Pfizer, Servier, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pullarkat:AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen, Dova, and Novartis: Consultancy, Other: Advisory Board Member. Piris-Villaespesa:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees. George:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; ARUP Laboratories: Other: Associated; Cogent Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patel:Cogent: Consultancy; Bristol Myers Squibb/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ustun:Blueprint: Honoraria; Cogent: Honoraria; Takeda: Speakers Bureau. Bose:NS Pharma: Research Funding; Morphosys: Honoraria, Research Funding; Kartos: Honoraria, Research Funding; Sierra Oncology: Honoraria; Karyopharm: Honoraria; Ionis: Research Funding; Incyte: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; PharmaEssentia: Honoraria; Cogent: Honoraria, Research Funding; Blueprint: Honoraria, Research Funding; BMS: Honoraria, Research Funding; AbbVie: Honoraria; Promedior: Research Funding. Heaney:Hoth Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Incyte Pharmaceuticals: Research Funding; Kartos Therapeutics: Research Funding; Novartis: Consultancy, Research Funding; PhrmaEssentia: Consultancy; Sierra Oncology: Consultancy, Research Funding; Cogent Biosciences: Consultancy, Research Funding; Blueprint Medicines: Consultancy, Research Funding; BMS: Research Funding; CTI Pharma: Consultancy, Research Funding. Sachs:Cogent Biosciences: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Sun:Cogent Biosciences: Current Employment. Pilla:Cogent Biosciences: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Exter:Cogent Biosciences: Current Employment. Jolin:Cogent Biosciences: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Tashi:Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees.

Bezuclastinib (CGT9486) is an investigational agent