Updated findings from the open-label extension of the phase 2 Summit trial reveal that a 100-mg dose of bezuclastinib provides significant relief from symptoms and reduces biomarkers associated with mast cell burden in individuals with non-advanced systemic mastocytosis. The research, presented at the 2024 ASH Annual Meeting, highlights the potential of bezuclastinib as a targeted therapy for this condition.
Symptom Relief and Biomarker Reduction
Bezuclastinib at 100 mg led to rapid, deep, and sustained reductions in serum tryptase over 24 weeks of treatment. Specifically, 89% of patients experienced at least a 50% decrease in serum tryptase levels within the first 4 weeks of treatment. Furthermore, among patients with baseline serum tryptase levels of at least 20 ng/mL, 95% achieved levels below 20 ng/mL with bezuclastinib.
Patients also reported sustained improvements in symptom severity. The MS2D2 Total Symptom Score decreased by a mean of 27.6 points in patients receiving active treatment for 24 weeks, with a median reduction from baseline of 55.8%. Notably, nearly one-third of patients were able to reduce or discontinue their best supportive care medications by week 24.
Improved Quality of Life
Treatment with bezuclastinib also led to improvements in health-related quality of life. Patients experienced a reduction in MC-QoL Total Score, indicating a shift from "moderate" to "mild" disease. The MC-QoL Total Score decreased by an average of 25.4 points during the 24-week treatment period, representing an average reduction of 48.9% from baseline.
Safety and Tolerability
The safety profile of bezuclastinib was encouraging, with most treatment-emergent adverse events (TEAEs) being low grade and reversible without dose modification. The most common TEAEs included nausea, hair color changes, peripheral edema, diarrhea, taste disorder, GERD, and neutropenia. Importantly, there were no reports of bleeding or cognitive impairment events.
Study Design
The Summit study is a phase 2, double-blind, placebo-controlled, randomized trial designed to evaluate bezuclastinib in non-advanced systemic mastocytosis. Part 1 of the study aimed to determine the recommended dose of bezuclastinib, enrolling patients with indolent or smoldering systemic mastocytosis who experienced moderate to severe symptoms despite being on two or more anti-mediator therapies. Patients were randomized to receive either 100 mg or 200 mg of bezuclastinib (original formulation), 100 mg or 150 mg (optimized formulation), or placebo, all in conjunction with best supportive care. The open-label extension focused on assessing the long-term safety and tolerability of bezuclastinib.
Baseline characteristics of the study participants included a median age of 52 years, with 66.7% being female. Most patients had an ECOG performance score of 1 (51.9%). A majority (77.7%) were positive for KIT D816V in whole blood, with a median bone marrow mast cell burden of 10% and a median serum tryptase at baseline of 37 ng/mL.
