Herrscher, Richard

Abstract Background: Systemic mastocytosis (SM) comprises a spectrum of subtypes characterized by neoplastic mast cell (MC) infiltration of tissues and release of MC mediators. Non-advanced SM (NonAdvSM), including indolent SM (ISM), smoldering SM (SSM), and bone marrow mastocytosis (BMM) subtypes, is the most prevalent form of SM. NonAdvSM can be associated with debilitating symptomology which can significantly impair quality of life. The gain-of-function somatic KIT c.2447 C>T (p.D816V) mutation is found in up to 95% of patients with SM. Bezuclastinib (CGT9486) is an oral, potent, and selective type 1 tyrosine kinase inhibitor with activity against KIT D816V. Results from Summit (NCT05186753) Part 1 informed the recommended phase 2 dose (100 mg QD bezuclastinib) for Part 2. We report topline results from the 24-week assessment of Summit Part 2. Methods: Summit is a multi-center, randomized, double-blind, placebo (PBO)-controlled Phase 2 trial of bezuclastinib in patients with NonAdvSM who had inadequate symptom control despite best supportive care (BSC) medications. The primary endpoint was 24-week mean change from baseline in Mastocytosis Symptom Severity Daily Diary (MS2D2) total symptom score (TSS) (range 0–110), which is a fit-for-purpose patient-reported outcome measure of NonAdvSM symptom severity. Key secondary endpoints included the proportion of patients with ≥50% reduction in serum tryptase, KIT p.D816V variant allele frequency (VAF), bone marrow (BM) MC burden, and MS2D2 TSS, ≥30% TSS reduction. Patients were randomized 2:1 to receive 100mg QD bezuclastinib + BSC or PBO + BSC. Results: As of May 22, 2025, 179 patients were enrolled in Part 2: 119 were randomized to receive 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 (SD) baseline MS2D2 TSS 55.6 (19.8); 82% of patients had ISM, 11% had BMM, and 7% had smoldering SSM. At baseline, median (range) KIT p.D816V VAF in whole blood, BM MC burden, and serum tryptase was 0.25% (0-34%), 10% (1-75%), and 40 (6-692) ng/mL, respectively. Bezuclastinib demonstrated statistically significant superiority to placebo on all primary and key secondary endpoints. At Week 24, bezuclastinib led to significantly greater symptom improvement vs placebo (LS mean [95% CI] MS2D2 TSS change: –24.3 [–27.6 to –21.1] vs –15.4 [–19.6 to –11.2]; placebo-adjusted difference: –8.9 points; P=0.0002). A ≥50% reduction in serum tryptase was achieved in 87.4% of bezuclastinib-treated patients vs 0% on placebo (P<0.0001). Significantly more patients receiving bezuclastinib achieved ≥50% reductions in KIT D816V VAF, serum tryptase, BM MCs (P<0.0001), MS2D2 TSS (P=0.01), and ≥30% reduction in MS2D2 TSS (P=0.0004). Most treatment-emergent adverse events (TEAEs) were low grade (gr; 70% Gr 1) and reversible. The most common TEAEs (≥10%) in any treatment group and occurring in greater frequency in the bezuclastinib arm were hair color changes (69.5% vs 5.0%), altered taste (23.7% vs 0%), nausea (22.0% vs 13.3%), increased ALT/AST (22.0% vs 6.6%), headache (17.8% vs 11.7%), alopecia (11.9% vs 3.3%), and increased ALP (10.2% vs 3.3%). TEAEs (≥10%) that occurred more often in the placebo group were diarrhea (13% vs 18%), dizziness (10% vs 12%), fatigue (7% vs 12%), and arthralgia (6% vs 15%). ALT/AST elevations ≥Gr 3 were experienced by 5.9% of patients. The only hepatic adverse events (AEs) reported were transient lab abnormalities; none required hospitalization. Treatment-related AEs requiring dose reductions occurred in 11% of patients receiving bezuclastinib. All discontinuations (5.9%) due to treatment-related AEs were due to transaminase elevations; all fully resolved. Conclusions: At 24-weeks, bezuclastinib 100 mg QD demonstrated statistically and clinically significant improvements in symptom burden and biomarkers of disease vs placebo in patients with NonAdvSM. The treatment was generally well-tolerated and effective across a population that is representative of the real-world NonAdvSM population, including SSM. These results support the use of bezuclastinib to reduce SM burden and symptoms in pts with NonAdvSM, and a potentially disease-modifying impact.

Background: Systemic mastocytosis (SM) is a rare disease characterized by neoplastic mast cell (MC) infiltration of extracutaneous tissues. Nonadvanced SM (NonAdvSM) is associated with debilitating symptoms which may significantly reduce health-related quality of life (HRQoL). In up to 95% of patients (pts), SM is driven by the somatic KIT c.2447 A>T (p.D816V) missense mutation. Bezuclastinib (bezu; CGT9486) is an oral, potent, small molecule, selective type 1 tyrosine kinase inhibitor (TKI) with activity against KIT D816V. Results from Part 1 of the 3-part Summit trial demonstrated that bezu is well-tolerated and is associated with encouraging clinical activity, including both reduced MC burden and improvement in symptoms over a 12-week (wk) period vs placebo (PBO). Based on safety, PK, biomarker, and efficacy results, a dose of 100mg QD bezu (optimized formulation) was selected for Summit Part 2. Trial Design and Methods: Summit (NCT05186753) is a multi-center, Phase 2, double-blind, PBO-controlled RCT of bezu in pts with NonAdvSM who have inadequate control of symptoms despite treatment with best supportive care (BSC). A novel pt-reported outcome measure, the Mastocytosis Symptom Severity Daily Diary (MS2D2), was designed to assess disease-specific symptom severity in NonAdvSM pts. Eleven symptoms are included in the MS2D2 Total Symptom Score (TSS). Summit Part 1a randomized pts 1:1:1 to PBO, 100mg, or 200mg, original formulation while Part 1b randomized 1:1:1 to PBO, 100mg, or 150mg, optimized formulation. Pts completing Part 1 of the Summit trial were allowed to receive bezu in the open-label extension (OLE) Part 3 of the trial. Results: As Part 2 will evaluate safety and efficacy of 100 mg bezu at 24 wks, this abstract reports on pts treated with both bezu formulations at 100mg in Parts 1a or 1b, which had similar PK exposures. The presentation will focus on 24-wk outcomes in pts receiving the selected 100 mg bezu dose and participating in the OLE. In Summit Part 1, 19 pts received PBO and 18 received 100 mg bezu for 12 wks. At baseline (BL), the symptoms identified as most severe were within the skin and fatigue domains. At BL, pts were managing their symptoms of NonAdvSM with 2 (43%), 3 (24%), or ≥4 (32%) BSC medications. At the 12-wk assessment in Part 1 (datacut 18Dec2023), the safety and tolerability profile was encouraging, with the majority of TEAEs low grade and reversible without dose modification. The most common TEAEs (>10% in 100 mg bezu) included hair color changes, nausea, diarrhea, peripheral edema, GERD, taste disorder, and neutropenia. There were no reported bleeding or cognitive impairment events. Of 37 pts randomized to PBO or 100 mg QD bezu, 36 (97%) received bezu in the OLE; one pt randomized to the 100 mg original formulation dose reduced and subsequently discontinued due to TEAE of ALT increase. All 19 PBO pts (100%) crossed over to receive bezu in the OLE; of these, 9 were randomized to the 100mg QD bezu dose. Reduction in MC burden was robust among those treated with 100mg bezu - 94.4%, 100%, and 92.3% of pts had at least a 50% reduction in basal serum tryptase, KIT p.D816V variant allele frequency, and bone marrow MCs, respectively. Pts treated with 100 mg bezu had reduction in MS2D2 TSS by 49.1% vs 21.1% with PBO. On a 0-10 scale, the most severe MS2D2 symptom mean change from BL was -3.03 from a BL mean of 7.6 with bezu vs -1.04 from a BL mean of 7.7 with PBO. Individual symptoms of the MS2D2 TSS, as well as others not in the TSS including diarrhea and brain fog, improved more with bezu than with PBO; mean change from BL ranged from -1.66 to -2.69 with bezu vs. a range of -0.52 to -1.58 with PBO. LS mean change from BL in quality of life (Mastocytosis (MC)-QoL, a disease-specific measure) was -22.05 in pts treated with 100mg bezu versus -10.71 in pts treated with PBO. Objective measurements of skin lesions, including centrally adjudicated longitudinal assessments of skin photography, also significantly reduced on bezu. Conclusions: In Part 1 (12 wk assessment), treatment with 100mg bezu resulted in favorable safety and tolerability, significant and deep reductions across all markers of MC burden, and clinically meaningful reduction in all individual MS2D2 TSS symptoms and across domains. The presentation will report on durability and safety/tolerability data beyond 12 wks for those pts randomized to 100 mg in Part 1 and pts who crossed over from PBO in Part 1 to 100mg in Part 3. Summit Part 2 is actively enrolling.