Apex Part 1: Updated Assessment of Bezuclastinib (CGT9486), a Selective KIT D816V Tyrosine Kinase Inhibitor, in Patients with Advanced Systemic Mastocytosis (AdvSM)

Background: Systemic mastocytosis (SM) is a rare disease characterized by the abnormal accumulation of mast cells (MC). In about 95% of adult patients, SM is driven by a gain-of-function mutation (D816V) in exon 17 of KIT. Advanced SM (AdvSM) is a life-threatening form of SM and includes three subtypes: aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Bezuclastinib is an oral, potent, and selective tyrosine kinase inhibitor (TKI) with activity against KIT D816V that spares closely related kinases and has minimal brain penetration. Initial results from the Part 1 dose optimization portion of the Apex trial (NCT04996875) in patients with AdvSM demonstrated an encouraging safety profile and signs of clinical activity as well as deep reductions across biomarkers of mast cell burden including the proportion of bone marrow mast cells, serum tryptase levels, and KIT D816V variant allele fraction (VAF). Herein we report updated safety and efficacy results from the fully enrolled Part 1 of the Apex trial.

Methods: Apex is a randomized Phase 2, open-label, multicenter trial in adult patients diagnosed with AdvSM per WHO criteria. In Part 1, patients were randomized 1:1:1:1 to bezuclastinib 50mg BID, 100mg BID, 200mg BID, or 400mg QD. Part 2 evaluated an optimized formulation of bezuclastinib at doses of 150mg and 300 mg. TKI-naïve patients and those with a history of prior TKI therapy (e.g., avapritinib, midostaurin) or other treatments were permitted in the trial after appropriate washout. The primary efficacy endpoint for this trial is ORR [complete response [CR] + CR with incomplete hematologic recovery [CRh] + partial response [PR] + clinical improvement [CI]) as assessed by the central response review committee (CRRC) based on mIWG-MRT-ECNM response criteria]. Responses require 12-week confirmation.

Results: In Part 1, a total of 32 patients were enrolled with AdvSM (ASM, n=7; SM-AHN, n=23; MCL, n=2) by central adjudication and were randomized and dosed with 50mg BID (n=8), 100mg BID (n=7), 200mg BID (n=8), or 400mg QD (n=9). Median age was 68 years (range, 33-87), 66% were male, and 84% had ECOG PS 0-1. Median KIT D816V VAF was 6.1% (range, 0-47.2%) and 91% of patients were positive for KIT D816V in peripheral blood at baseline. At baseline, 69% of patients had never received midostaurin and/or avapritinib, while 31% had prior midostaurin only and 16% had both prior avapritinib and midostaurin. Of those enrolled, 27 (84%) patients were mIWG-MRT-ECNM-evaluable, exhibiting 1 or more mIWG organ damage finding(s). As of 18Jun2024, median treatment duration was 60 (range, 0.3 - 124.1) weeks. In all Part 1 patients across dose levels, 94%, 93%, and 100% of patients achieved at least 50% reduction in serum tryptase, KIT D816V VAF, and bone marrow mast cell burden, respectively. Treatment-related adverse events (TRAEs) were reported in 91% of patients; 44% had TRAEs of at least grade 3. The most common TRAEs reported in >10% patients (% all grades, % grade ≥3) were hair color changes (34%, 0%), neutropenia (25%, 9%), thrombocytopenia (25%, 6%), ALT/AST increased (28%, 6%), fatigue (16%, 0%), periorbital edema (13%, 3%), peripheral edema (13%, 0%), and dysgeusia (13%, 0%). No treatment-related cognitive impairment or intracranial bleeding events were reported. Overall, 11 (34%) patients dose reduced and 2 (6%) discontinued due to TRAEs [1 Gr3 drug induced liver injury (DILI); 1 Gr3 ALT/AST increased]. No treatment-related deaths occurred. In the 27 mIWG-MRT-ECNM evaluable patients enrolled in the study, the ORR is 52% (14/27). Median time to the start of confirmed response was 2.1 (range 1.9-4.8) months. Median duration of response was not yet reached in response-evaluable patients (range 2.8 to 19.4 months). The rate of pure pathologic response (CR/CRh+PR) was 88% (28/32).

Conclusion: In Part 1 of the Apex trial, bezuclastinib is well tolerated and exhibits durable signs of clinical activity, with marked reductions in objective measures of mast cell burden. Based on a composite of safety/tolerability, efficacy, and pharmacokinetics, 150 mg daily has been chosen as the recommended dose.

DeAngelo:MT Sinai MPN Consortium: Other: DSMB; Fibrogen: Other: DSMB; Daiichi-Sankyo: Other: DSMB; Glycomimetics: Research Funding; Abvie: Research Funding; Bristol-Meyers Squibb: Honoraria; Takeda: Consultancy; Servier: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Kite: Consultancy; Incyte: Consultancy; Jazz: Consultancy; Gilead: Consultancy; Curis: Consultancy; Blueprint: Consultancy, Research Funding; Autolos: Consultancy; Amgen: Consultancy, Honoraria. Pullarkat:Novartis: Consultancy, Honoraria; Amgen: Speakers Bureau; Sobi: Speakers Bureau; Jazz: Speakers Bureau; Alexion: Honoraria; Abbvie: Consultancy, Honoraria, Speakers Bureau; Rigel: Consultancy, Honoraria. Vachhani:CTI BioPharma Corp (now Sobi): Consultancy, Research Funding; Takeda: Research Funding; Stemline: Consultancy; GlaxoSmith Kline: Consultancy; Karyopharm: Consultancy; MorphoSys: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Astex Pharmaceuticals: Research Funding; Kartos Therapeutics: Research Funding; Gilead/Forty Seven: Research Funding; GenenTech: Consultancy; Seattle Genetics: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Cogent Biosciences: Consultancy; Amgen: Consultancy, Research Funding; Blueprint Medicines: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding. Tashi:Italfarmaco: Research Funding; Telios: Research Funding; CITI Biopharma: Honoraria; Cogent: Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Blueprint: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Study Steering Committee, Research Funding. Lee:Medison: Consultancy; Novartis: Consultancy; Forus Therapeutics: Membership on an entity's Board of Directors or advisory committees. Hunter:GSK: Consultancy, Honoraria; PharmaEssentia: Consultancy, Honoraria; Blueprint Medicines: Consultancy, Honoraria, Research Funding; Sobi​ (formerly CTI biopharma): Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Cogent Biosciences: Research Funding; Ascentage Pharma: Research Funding; Syntrix Biosystems: Research Funding; Novartis: Research Funding; PharmaEssentia: Research Funding. Piris-Villaespesa:Novartis: Consultancy, Speakers Bureau; BluePrint: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Speakers Bureau. Cridtina:BluePrint: Consultancy; AS Science: Consultancy. Shoumariyeh:Blueprint: Honoraria. Lambert:Kite-Gilead: Consultancy, Honoraria; Blueprint: Consultancy; Novartis: Honoraria; Takeda: Honoraria. George:Blueprint Medicines Corporation: Consultancy; Cogent Biosciences: Consultancy; Beckman Coulter: Consultancy; Celgene/BMS: Consultancy; Incyte: Consultancy. Patel:BMS: Consultancy. Papayannidis:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; Menarini/Stemline: Honoraria; BMS: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Delbert Laboratories: Membership on an entity's Board of Directors or advisory committees. Jain:Bristol Myers Squibb, Incyte, Abbvie, CTI, Kite, Cogent Biosciences, Blueprint Medicine, Telios pharma, Protagonist therapeutics, Galapagos, Tscan therapeutics, Karyopharm, Morphosys: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma, Kartos therapeutics, Incyte, Bristol Myers Squibb: Research Funding. Deininger:SPARC: Research Funding; Leukemia & Lymphoma Society: Research Funding; Fusion Pharma: Consultancy; DisperSol: Consultancy; Takeda: Honoraria, Other: Part of a study management committee, Research Funding; Sangamo: Consultancy, Honoraria; Medscape: Honoraria, Other: Case Author ; Incyte: Honoraria, Research Funding; Blueprint Medicines Corporation: Consultancy, Honoraria, Other: Part of a study management committee, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grants, Travel, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grants, travel, clinical trial support, Research Funding. Reiter:Novartis: Consultancy, Honoraria, Other: Grants (institution) , Research Funding; Abbvie: Research Funding; Blueprint Medicines Corporation: Consultancy, Other: Grants (institution) , Research Funding; Cogent Therapeutics LLC: Research Funding; AOP: Consultancy, Honoraria, Other: travel grants, Research Funding; Astra Zeneca: Research Funding; BMS: Research Funding; GSK: Consultancy, Honoraria, Other: travel expense, Research Funding; Incyte: Research Funding. Hobbs:Pharmaessentia: Honoraria; Pfizer: Honoraria; GSK: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria; Abbvie: Honoraria; Sobi: Honoraria; Novartis: Honoraria; Cogent: Honoraria; Regeneron: Other: spouse employment. Sun:Cogent: Current Employment, Current equity holder in publicly-traded company. Nagendra:Cogent: Current Employment, Current equity holder in publicly-traded company. Zhang:Cogent: Current Employment, Current equity holder in publicly-traded company. Pilla:Cogent: Current Employment, Current equity holder in publicly-traded company. Dishman:Cogent: Current Employment, Current equity holder in publicly-traded company. Carden:Cogent: Current Employment, Current equity holder in publicly-traded company. Radia:Cogent: Consultancy, Honoraria, Other: Study Steering Committee; Novartis: Honoraria; Blueprint: Consultancy, Honoraria, Other: Study Steering Committee, Research Funding, Speakers Bureau.