Abstract Background: Systemic mastocytosis (SM) includes a spectrum of hematologic malignancies characterized by a variable degree of neoplastic mast cell (MC) infiltration of extracutaneous tissues. The gain-of-function somatic KIT c.2447 CT (p.D816V) mutation drives SM in the majority of patients. Most SM patients have a non-advanced SM (NonAdvSM) subtype which includes bone marrow mastocytosis (BMM), indolent SM (ISM), and smoldering SM (SSM). Pathological and molecular markers of disease burden including the degree of bone marrow (BM) MC infiltration, serum tryptase elevation, and KIT p.D816V variant allele frequency (VAF) detection are used to determine the NonAdvSM subtype, serve as key indicators of disease severity, and correspond to the risk of progression and survival. The percentage of patients who experience pathological as well as pathological and molecular remission of NonAdvSM following treatment with a tyrosine kinase inhibitor has not yet been described. Bezuclastinib (CGT9486) is an oral, potent, and selective type 1 tyrosine kinase inhibitor with activity against KIT D816V. The Summit trial (NCT05186753) is a double-blind, placebo-controlled randomized clinical study evaluating bezuclastinib in patients with the full spectrum of NonAdvSM, including patients with SSM. Here, we describe the effect of bezuclastinib on serum tryptase, KIT p.D816V VAF, and BM MCs in the Summit Part 2 clinical trial. Methods: Summit was designed to evaluate safety and efficacy of bezuclastinib in patients with NonAdvSM who have inadequate symptom control despite optimized best supportive care medications. Inclusion criteria allowed for enrollment of patients with SSM, ISM, and BMM. Patients were randomized 2:1 to receive 100mg QD bezuclastinib + BSC or placebo + BSC. The primary endpoint was the 24-wk mean change from baseline (BL) in Mastocytosis Symptom Severity Daily Diary (MS2D2) total symptom score (TSS) (range 0–110). Key secondary endpoints included the proportion of patients with ≥50% reduction in serum tryptase, KIT p.D816V variant allele frequency (VAF), BM MC burden, and MS2D2 TSS, ≥30% TSS reduction. Serum tryptase, KIT p.D816V VAF, and BM biopsy were obtained at baseline and week 24 to determine the effect of bezuclastinib vs. placebo on pathologic measures of disease. MC aggregation, morphology and immunophenotype were assessed. Immunohistochemical staining for CD117, tryptase, CD25, CD30, and CD34 was performed on BM sections using standard techniques. Results: As of May 22, 2025, 179 patients were enrolled in Summit Part 2: 119 were randomized to bezuclastinib and 60 to placebo. Patients enrolled were representative of the NonAdvSM population with moderate to severe symptoms. Median age (range) was 51 (23-78) years; 65.9% female; mean (range) baseline MS2D2 TSS 55.6 (13-105); 82% of patients had ISM, 11% had BMM, and 7% had SSM. At baseline, median (range) KIT p.D816V VAF in peripheral blood was 0.25% (0-34%); 77.7% (139/179) of patients had detectable KIT p.D816V in peripheral blood at baseline. Median (range) BM MC burden at baseline was 10% (1-75%). 75% (135/179) of patients had MC aggregates at baseline. Median (range) serum tryptase at baseline was 40 (6-692) ng/mL; serum tryptase level was ≥20 ng/mL in 82.1% (147/179). Reduction in serum tryptase by 50% or greater was achieved in 87.4% of patients randomized to bezuclastinib compared with 0% of patients randomized to placebo after 24 weeks of treatment (p0.0001). Conclusions: Substantial reductions of KIT p.D816V VAF in some cases to undetectable levels, normalization of serum tryptase, as well as normalization of BM MC percentage and morphology may represent potential reversal of the underlying pathogenesis of SM. The effect of bezuclastinib treatment on these disease markers and changes in BM MC characteristics will be presented. The impact of treatment on the WHO criteria which define SM supports the mechanism of action of the targeted KIT inhibitor bezuclastinib as a disease-modifying investigational therapeutic in NonAdvSM. The correlation between reductions in bone marrow MC infiltration, serum tryptase, and KIT p.D816V VAF and the patient-reported symptom response will be explored.
George et al. (Mon,) studied this question.