Researchers have reported early data suggesting that bezuclastinib achieves clinically meaningful improvements in patients with advanced systemic mastocytosis (SM), according to a study published in Blood.

SM is overwhelmingly driven by a gain-of-function mutation (D816V) in exon 17 of the KIT gene (more than 95% of cases). Advanced SM has 3 distinct categories: aggressive SM, SM with an associated hematologic neoplasm, and mast cell leukemia. 

Bezuclastinib is a newly developed, highly selective tyrosine kinase inhibitor. It has specificity for the most common mutations in SM, encompassing mutations in KIT exons 9, 11, 17, and 18. A phase 1/2 study assessing the merits of bezuclastinib in patients with advanced SM has led to continued evaluation of this potential therapy in this patient population. 

The authors of this study sought to investigate the efficacy and safety of bezuclastinib across the 3 main subtypes of advanced SM. This open-label, multicenter study included patients diagnosed with advanced SM according to World Health Organization (WHO) guidelines. 

Read more about systemic mastocytosis diagnosis 

There were 2 parts to this study: the first involved patients randomized 1:1:1:1 to receive bezuclastinib 50, 100, or 200 mg twice a day or 400 mg once a day, while dosing for the second phase will be informed by data from Part 1. The endpoints of this study encompassed various clinical parameters measuring treatment response. 

The research team recruited 11 patients, as of May 24, 2022, to participate in the first part of the study. They discovered that bezuclastinib was well tolerated at all 4 doses prescribed. In addition, all 11 patients had more than a 50% reduction in serum tryptase levels from baseline. 

“Among patients with available data after ≥2 cycles of treatment, all 8 achieved a median reduction of 68% in KIT D816V variant allele fraction (VAF) and ≥50% reduction in [bone marrow mast cells], with 6/8 (75%) achieving complete clearance of [mast cell] aggregates,” the authors of the study wrote. 

The research team concluded that early results of the efficacy and safety of bezuclastinib in patients with advanced SM were promising. Enrollment for the next phase of the study is ongoing. 


DeAngelo DJ, Pullarkat VA, PirisVillaespesa M, et al. Preliminary safety and efficacy from Apex, a phase 2 study of bezuclastinib (CGT9486), a novel, highly selective, potent KIT D816V tyrosine kinase inhibitor, in adults with advanced systemic mastocytosis (AdvSM). Blood. 2022;140(Suppl 1):1512-1513. doi:10.1182/blood-2022-156311