Bezuclastinib normalized key bone marrow pathology in nonadvanced systemic mastocytosis.
Treatment with bezuclastinib led to reversals in key bone marrow pathology for patients with nonadvanced systemic mastocytosis, according to data from the phase 2 SUMMIT (NCT05186753) trial presented at the
Findings showed that at baseline, 74% of evaluable patients (n = 119) treated with bezuclastinib had mast cell aggregates in their bone marrow at baseline compared with 78% of patients treated with placebo (n = 60). At week 24, these rates were 13% for bezuclastinib (n = 101) and 60% for placebo (n = 51).
The mean mast cell level in the bone marrow at baseline was 18% in the bezuclastinib arm (n = 119) vs 16% in the placebo arm (n = 60); at week 24, these rates were 5% for bezuclastinib (n = 102) and 14% for placebo (n = 50). Additionally, the mean spindled-shaped mast cell levels in the bone marrow at baseline were 76% in the bezuclastinib arm (n = 119) vs 75% in the placebo arm (n = 60); at week 24, these rates were 50% for bezuclastinib (n = 95) and 70% for placebo (n = 50).
“These data [from both analyses of SUMMIT] are very strong, and [they] show that bezuclastinib is a good treatment for patients with nonadvanced systemic mastocytosis,” lead study author Tracy George, MD, said in an interview with OncLive®. “We’re seeing really nice correlates with the mast cell data and the biomarkers…[bezuclastinib] is eliminating mast cells in the bone marrow, and as you eliminate more…it correlates really well with the decrease in TSS.”
George is president of the Innovation Business Unit and chief scientific officer at ARUP Laboratories, as well as a professor of pathology at the Spencer Fox Eccles School of Medicine at the University of Utah in Salt Lake City.
Part 2 of the SUMMIT trial enrolled patients with indolent systemic mastocytosis, bone marrow mastocytosis, or smoldering systemic mastocytosis per World Health Organization (WHO) 2022 classification.1 Patients also needed to have inadequate symptom control despite receipt of at least 2 anti-mediator therapies.
Patients were randomly assigned 2:1 to receive bezuclastinib at 100 mg once per day plus best supportive care (BSC; n = 119) or placebo plus BSC (n = 60). The double-blind treatment period lasted for 24 weeks.
The primary end point of part 2 of SUMMIT was the mean change in Mastocytosis Symptom Severity Daily Diary (MS2D2) total symptom score (TSS) from baseline to week 24. Secondary end points included the rates of patients to experience at least a 50% reduction in serum tryptase levels, at least a 50% reduction in KIT p.D816V variant allele frequency (VAF), at least a 50% reduction in bone marrow mast cell burden, at least a 50% reduction in MS2D2 TSS, and at least a 30% reduction in TSS.
The median age was 51 years (range, 24-73) in the bezuclastinib arm vs 52 years (range, 23-78) in the placebo arm. Most patients in both arms were female (bezuclastinib, 62.2%; placebo, 73.3%), had indolent systemic mastocytosis (81.5%; 83.3%), had KIT p.D816V variants detected in whole blood (76.5%; 80.0%), and had a myelofibrosis grade of MF-1 (55.0%; 55.0%). The median KIT p.D816V VAF was 0.22% (range, 0%-32.28%) in the bezuclastinib arm vs 0.30 (range, 0%-33.59%) in the placebo arm.
George also explained that the reductions in CD25 and CD30 expression in the bezuclastinib arm supported the agent’s ability to drive mast cell modulation and impact the disease. At baseline in the bezuclastinib arm (n = 100), the mean CD25 and CD30 expressions were 89% and 13%, respectively. At week 24, these rates were 23% and 3%, respectively. At baseline in the placebo arm (n = 50), the respective mean CD25 and CD30 expressions were 87% and 12%; at week 24, these respective rates were 93% and 16%.
Furthermore, the mean bone marrow cellularity was 52% at baseline in the bezuclastinib arm (n = 119) vs 50% in the placebo arm (n = 60); at week 24, these rates were 40% for bezuclastinib (n = 102) and 49% for placebo (n = 51; P < .0001). In patients with smoldering systemic mastocytosis, the baseline mean bone marrow cellularity rates were 73% for bezuclastinib (n = 8) vs 71% for placebo (n = 4); at week 24, these respective rates were 40% for bezuclastinib (n = 6) and 70% for placebo (n = 3; P = .02).
By week 24, 39% of patients in the bezuclastinib arm had any myelofibrosis grade compared with 62% at baseline, and these changes were minimal in the placebo arm.
KIT p.D816V VAF reductions of at least 50% occurred at week 24 in 97% of evaluable patients in the bezuclastinib arm (n = 64) vs 3% in the placebo arm (n = 33). Within these evaluable subgroups, 30% of patients in the bezuclastinib group had undetectable KIT p.D816V compared with 0 patients in the placebo group.
For patients with elevated serum tryptase levels of at least 20 ng/mL at baseline, 83% of patients in the bezuclastinib arm (n = 89) experienced normalization below this level by week 24. In those with elevated levels of at least 11.4 ng/mL at baseline (n = 104), reductions below this level were observed in 78% of patients.
The overall response rate was 91% in the bezuclastinib arm among evaluable patients (n = 57) compared with 0% in the placebo group (n = 31). In the bezuclastinib arm, the rates of complete remission and partial remission were 67% and 25%, respectively. The rates of stable disease were 9% for bezuclastinib and 100% for placebo. Notably, at week 24, 55% of patients in the bezuclastinib arm (n = 100) did not meet WHO diagnostic criteria for nonadvanced systemic mastocytosis compared with 4% of patients in the placebo arm (n = 50).
“It’s very interesting to see [these data] as a pathologist, because many of these bone marrows [of patients] treated with bezuclastinib look normal,” George said. “I would never have known that these patients had [nonadvanced] systemic mastocytosis at baseline.”
