Bezuclastinib Exhibits Superior Disease Biomarker Reduction in NonAdvSM, With Tracy George, MD

A primary analysis of the phase 3 SUMMIT trial has shown that patients with non-advanced systemic mastocytosis (NonAdvSM) who received treatment with bezuclastinib exhibited improvements in symptom burden and biomarkers of disease compared to placebo.1

Presented at the 67th American Society of Hematology (ASH) Annual Meeting and Exposition by Tracy George, MD, professor at the University of Utah and vice chair of clinical affairs at the University of New Mexico, these data support the use of bezuclastinib to reduce NonAdvSM disease burden, thereby taking advantage of its possibly disease-modifying impact.1,2

“This is really exciting work, because not only do patients with non-advanced systemic mastocytosis respond clinically to bezuclastinib, but we are actually seeing disease modification in the bone marrow,” George told HCPLive in an exclusive interview. “Bone marrow mast cells are removed from the bone marrow, change their shape to become normal, and they normalize their immunophenotype. And so, you go from bone marrows which are hypercellular with dense mast cell aggregates to bone marrows which are normally cellular and essentially look normal after treatment with bezuclastinib.”

George’s presentation was based on the registration-directed part 2 of the SUMMIT trial. Investigators included patients with NonAdvSM who had inadequate symptom control despite best supportive care (BSC) mediations. The primary endpoint was 24-week mean change from baseline in Mastocytosis Symptom Severity Daily Diary (MS2D2) total symptom score (TSS), which is a patient-reported outcome measure of symptom severity in NonAdvSM.2

A total of 179 patients were included in part 2 of SUMMIT; of these, 119 received bezuclastinib once daily plus BSC, while 60 received placebo plus BSC. The median age was 51 (range, 23-78) years, and mean baseline MS2D2 TSS was 55.6 (standard deviation [SD], 19.8). Additionally, 82% of patients had indolent systemic mastocytosis, 11% had bone marrow mastocytosis, and 7% had smoldering systemic mastocytosis.2

At week 24, investigators saw significantly greater symptom improvement among patients treated with bezuclastinib compared to those receiving placebo (least squares mean MS2D2 TSS change: -24.3; 95% CI, -27.6 to -21.1 vs. -15.4; 95% CI, -19.6 to -11.2; P = .0001). A ≥50% reduction was also achieved in serum tryptase in 87.4% of bezuclastinib-treated patients versus 0% on placebo (P <.0001).2

Investigators also saw more patients receiving bezuclastinib achieved ≥50% reductions in KIT D816V variant allele frequency, serum tryptase, bone marrow MCs (P <.0001), MS2D2 TSS (P = .01), and ≥30% reduction in MS2D2 TSS (P = .0004).2

Additionally, most treatment-emergent adverse events were low grade and reversible. The most common in any treatment group were hair color changes (69.5% in bezuclastinib vs 5% in placebo), altered taste (23.7% vs 0%), nausea (22% vs 13.3%), increased ALT/AST (22% vs 6.6%), headache (17.8% vs 11.7%), alopecia (11.9% vs 3.3%), and increased ALP (10.2% vs 3.3%).2

Ultimately, George and colleagues determined that bezuclastinib exhibited statistically and clinically significant improvements in both symptom burden and disease biomarkers compared to placebo in patients with NonAdvSM.2

“What’s exciting is that these are the results from this pivotal SUMMIT trial, which was treating patients with non-advanced systemic mastocytosis,” George said. “What I’m really looking forward to is our results from the APEX trial, which is treating patients with advanced systemic mastocytosis with bezuclastinib. I expect it’s going to be exciting; I’m hoping to see similar results from that trial.”

Editor's Note: George reports disclosures with Incyte, Celgene/BMS, Beckman Coulter, Cogent Biosciences, and Blueprint Medicines.

References

1. George T, Boggs N, Patel J, et al. The effect of bezuclastinib on the pathobiology of mastocytosis: Changes in BM mast cells, tryptase, and KIT p.D816V variant allele frequency from the pivotal SUMMIT trial. Abstract presented at the 67th American Society of Hematology Annual Meeting. Orlando, FL. December 6-9, 2025.

2. Rein L, Boggs N, Bose P, et al. Efficacy and safety results from the primary analysis of the Pivotal Summit Trial: Bezuclastinib in adults with non-advanced systemic mastocytosis. Blood. 2025;146(Supplement 1):80-80. doi:10.1182/blood-2025-80