Abstract
Advanced systemic mastocytosis (AdvSM) is a rare, KIT D816V-driven hematologic neoplasm characterized by mast cell infiltration and shortened survival. We report the results of a prespecified interim analysis of an ongoing pivotal single-arm phase 2 trial (no. NCT03580655) of avapritinib, a potent, selective KIT D816V inhibitor administered primarily at a once-daily starting dose of 200 mg in patients with AdvSM (n = 62). The primary endpoint was overall response rate (ORR). Secondary endpoints included mean baseline change in AdvSM–Symptom Assessment Form Total Symptom Score and quality of life, time to response, duration of response, progression-free survival, overall survival, changes in measures of disease burden and safety. The primary endpoint was successfully met (P = 1.6 × 10-9), with an ORR of 75% (95% confidence interval 57–89) in 32 response-evaluable patients with AdvSM who had sufficient follow-up for response assessment, including 19% with complete remission with full or partial hematologic recovery. Reductions of ≥50% from baseline in serum tryptase (93%), bone marrow mast cells (88%) and KIT D816V variant allele fraction (60%) were observed. The most frequent grade ≥3 adverse events were neutropenia (24%), thrombocytopenia (16%) and anemia (16%). Avapritinib demonstrated a high rate of clinical, morphological and molecular responses and was generally well tolerated in patients with AdvSM.
Highlights
Systemic mastocytosis (SM) is a rare hematologic neoplasm that is associated with the KIT D816V mutation in ~95% of cases
Between 21 November 2018 and 23 June 2020, 62 patients with prospectively centrally adjudicated Advanced systemic mastocytosis (AdvSM) were enrolled (ASM (n = 9), SM with an associated hematologic neoplasm (SM-AHN) (n = 43) and mast cell leukemia (MCL) (n = 10)) and received avapritinib primarily at a starting dose of 200 mg QD (n = 60; two patients started at 100 mg QD), across cohort 1 (n = 52) and cohort 2 (n = 10) (Extended Data Fig. 1)
94% were positive for the KIT D816V mutation and 53% carried an additional mutation in at least one of the genes SRSF2, ASXL1 or RUNX1 (S/A/R), which is associated with poor survival in SM12
Summary
Systemic mastocytosis (SM) is a rare hematologic neoplasm that is associated with the KIT D816V mutation in ~95% of cases. In AdvSM, mast cell infiltration leads to organ damage, referred to as ‘C-findings’ (that is, cytopenias or liver dysfunction), with limited treatment options and poor survival. AdvSM is comprised of three subtypes: aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL). In this trial, avapritinib exhibited an ORR of 75% by modified (m)IWG–MRT–ECNM (International Working Group–Myeloproliferative Neoplasms Research and Treatment and European Competence Network) criteria, including 36% with complete remission with full (CR) or partial hematologic recovery (CRh), with a median follow-up of 23 months. Patients experienced profound reductions in objective measures of mast cell burden, including complete molecular remission of KIT D816V, reversion of mast-cell-related organ damage and improvements in symptoms. Rapid reduction of disease burden and response rate led to selection of 200 mg as the optimal dose for patients with AdvSM. All enrolled patients (safety population) were included in secondary endpoints, which included changes in patient symptoms, reduction in measures of disease burden and safety
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