The FDA set a target action date of June 29, 2027, for bezuclastinib's NDA in advanced systemic mastocytosis, backed by APEX trial data.
The FDA has accepted a new drug application (NDA) for bezuclastinib for patients with advanced systemic mastocytosis.1 Additionally, the agency assigned a Prescription Drug User Fee Act target action date of June 29, 2027.
The regulatory decision was supported by data from the phase 2 APEX trial (NCT04996875), which were presented at the
All evaluable patients in the trial (n = 81) achieved an ORR of 81% per Pure Pathologic Response (PPR) criteria, including a CR/CRh rate of 62%. The PR rate for these patients was 20%, and 17% of patients experienced stable disease.
“With the FDA’s acceptance of our NDA in advanced systemic mastocytosis, we have reached another important regulatory milestone for bezuclastinib and are one step closer to potentially bringing this therapy to patients,” said Andrew Robbins, president and CEO of Cogent Biosciences, in a news release.1 “Together with the NDAs currently under review for
Interested in data for bezuclastinib in GIST? Be sure to watch
The multicenter, open-label study of bezuclastinib enrolled patients patients with aggressive systemic mastocytosis, systemic mastocytosis with associated hematologic neoplasms, or mast cell leukemia per World Health Organization 2022 classification with no restrictions on prior therapy. Eligible patients also required a serum tryptase level of at least 20 ng/mL and a platelet count of at least 50 × 109/L.2
If patients had persistent toxicities or clinically significant cardiac disease, had received cytoreductive therapy or investigational agents less than 2 weeks prior to screening bone marrow biopsy, or had received strong CYP3A4 inhibitors or inducers within 2 weeks of their first dose, they were not included in the trial.3
In part 2 of the trial, 81 patients were treated with a confirmed dose of bezuclastinib 150 mg once daily.2 A cohort of patients with aggressive systemic mastocytosis or systemic mastocytosis with associated hematologic neoplasms who had mIWG-MRT-ECNM–measurable disease, or patients with mast cell leukemia (n = 58), were enrolled, plus a separate cohort of patients with aggressive systemic mastocytosis or systemic mastocytosis with associated hematologic neoplasms without measurable disease (n = 13).
The primary end point was ORR per mIWG-MRT-ECNM criteria, which consisted of CR, CRh, PR, and clinical improvement.
Secondary end points included ORR per PPR criteria, time to response, duration of response, changes in bone marrow mast cell burden, serum tryptase, and KIT p.D816V variant allele frequency, progression-free survival (PFS), overall survival (OS), and safety.
For all evaluable patients (n = 81), the median age was 70 years (range, 43-87); 70% of patients had systemic mastocytosis with associated hematologic neoplasms, 16% had mast cell leukemia, and 14% had aggressive systemic mastocytosis. Most patients had an ECOG performance status of 1 (49%) or 0 (27%).
Median bone marrow mast cell burden was 35% (range, 3%-95%), and median serum tryptase was 191 ng/mL (range, 23-1987); 35% of patients had received prior tyrosine kinase inhibitor therapy for advanced systemic mastocytosis or an associated hematologic neoplasm.
In evaluable patients (n = 68), 12-month PFS and OS rates per mIWG-MRT-ECNM criteria were 79% (95% CI, 65.5%-87.6%) and 87% (95% CI, 77.8%-93%).2
Across all patients treated with bezuclastinib (n = 81), treatment-related adverse effects (TRAEs) of any grade occurred in 93%, including serious TRAEs in 7%. TRAEs led to dose reductions in 16% of patients, and discontinuation in 1%, with the majority remaining on their starting dose over a median treatment duration of 63.0 weeks (range, 1.0-135.3).
The most common any-grade hematologic TRAEs were neutropenia (31%), thrombocytopenia (25%), and anemia (16%). These TRAEs at grade 3 or higher occurred at respective rates of 24%, 14%, and 10%.
Common nonhematologic TRAEs included hair color changes (31%), altered taste (28%), increased alanine aminotransferase/aspartate aminotransferase (21%) levels, increased alkaline phosphatase (14%), diarrhea (16%), and nausea (15%). Treatment-related hepatic events were reported as transient, manageable laboratory abnormalities; no treatment-related grade 4 hepatic AEs or deaths were observed.
