Background: Systemic mastocytosis (SM) is a rare disease characterized by the aberrant 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 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. Preliminary results from the on-going Apex study in patients with AdvSM (NCT04996875) were presented previously (DeAngelo et al. [abstract] In: Blood (ASH) 2022; 140 (Supplement 1): 1512-13).

Methods: Apex is a randomized Phase 2, open-label, multicenter trial in adult patients diagnosed with AdvSM per 2022 WHO criteria with a baseline serum tryptase of ≥20 ng/mL. In Part 1, patients were randomized 1:1:1:1 to bezuclastinib 50mg BID, 100mg BID, 200mg BID, or 400mg QD. Patients with a history of prior TKI therapy (e.g., avapritinib, midostaurin) are permitted in the trial. Data from Part 1 informed dose selection for Part 2 of the trial. The primary efficacy endpoint for this trial 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 review committee based on mIWG-MRT-ECNM response criteria.

Results: As of April 2023, Part 1 was fully enrolled with 33 AdvSM patients. Patients were randomized to 50mg BID (n=8), 100mg BID (n=8), 200mg BID (n=8), or 400mg QD (n=9). Disease subtypes included ASM (n=7), MCL (n=2), and SM-AHN (n=24); AHN subtypes included CMML (n=18), MDS (n=3), MPN (n=1), and MDS/MPN-U (n=2). The majority of patients were male (64%), ECOG PS 0-1 (82%) and KITD816V positive at baseline (91%). At baseline, 67% of patients were TKI-naïve; 33% had prior midostaurin, and 15% had prior avapritinib. Median (range) BM MC burden, serum tryptase, and KIT D816V VAF at baseline were 30% (5-90), 163 ng/mL (35-1578), and 7% (0-47), respectively. Of the 33 patients enrolled, 25 patients (76%) had C-findings evaluable per mIWG-MRT-ECNM criteria; 20 patients (61%) were positive for SRSF2/ASXL1/RUNX1 mutation which are associated with poor survival in SM.

Conclusion: Enrollment in Part 1 of the Apex trial is complete. Patients enrolled in Part 1 of the Apex trial are generally representative of the population of patients with AdvSM based on patient characteristics and markers of disease. Part 1 includes a small subset of patients with prior use of TKIs. Safety, clinical activity, and clinical objective response for all patients in Part 1 will be presented.

Vachhani:LAVA therapeutics: Consultancy; MorphoSys: Consultancy; Stemline: Consultancy; Servier: Consultancy; Genentech: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; GlaxoSmith Kline: Consultancy; Daiichi Sankyo: Consultancy; CTI BioPharma Corp: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Cogent Biosciences: Consultancy; Blueprint Medicines: Consultancy, Speakers Bureau; Amgen: Consultancy; AbbVie: Consultancy. Tashi:Cogent: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees. Schiller:ElevateBio: Research Funding; Agios: Research Funding; Trovagene: Research Funding; Tolero Pharmaceuticals: Research Funding; Takeda: Research Funding; Stemline Therapeutics: Research Funding; Sellas Life Sciences: Research Funding; Sangamo Bioscience: Research Funding; Samus Therapeutics: Research Funding; REGiMMUNE: Research Funding; Precog: Research Funding; Pfizer: Research Funding; Onconova Therapeutics: Research Funding; Mateon Therapeutics: Research Funding; Geron: Research Funding; Genentech/Roche: Research Funding; Gamida Cell: Research Funding; Fujifilm: Research Funding; FORMA Therapeutics: Research Funding; Delta-Fly Pharma: Research Funding; Deciphera: Research Funding; Daiichi Sankyo: Research Funding; Constellation Pharmaceuticals: Research Funding; Celator: Research Funding; Arog: Research Funding; Actuate Therapeutics: Research Funding; Actinium Pharmaceuticals: Research Funding; Karyopharm Therapeutics: Research Funding, Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; Stemline Therapeutics: Speakers Bureau; Kite: Research Funding, Speakers Bureau; Astellas Pharma: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Agios: Consultancy; Ono Pharmaceutical: Consultancy; Ono Pharmaceutical: Research Funding; AVM Biotechnology: Research Funding; Syros Pharmaceuticals: Research Funding; Kronos Bio: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company, Research Funding; Bristol Myers Squibb: Current equity holder in publicly-traded company, Research Funding, Speakers Bureau. Lee:Medison: Consultancy. Piris Villaespesa:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees. Livideanu:Novartis: Research Funding; Lilly, Novartis, UCB: Consultancy; Blueprint Medicines Corporation: Membership on an entity's Board of Directors or advisory committees; ABScience: Membership on an entity's Board of Directors or advisory committees. Lambert:Takeda: Honoraria; Blueprint: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Kite-Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hunter:Sierra Oncology: Membership on an entity's Board of Directors or advisory committees. George:Blueprint Medicines Corporation: 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; Cogent Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; ARUP Laboratories: Current Employment. Shoumariyeh:Astrazeneca: Honoraria; BMS: Speakers Bureau; Blueprint: Consultancy; Novartis: Honoraria. Petroro: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. Jolin:Cogent: Current Employment, Current equity holder in publicly-traded company. Easton:Cogent: Current Employment, Current equity holder in publicly-traded company. Pullarkat:Servier: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau.

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2023
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