The Lynx Group

Avapritinib Effectively Manages Advanced Systemic Mastocytosis in Patients with KIT D816V Mutations

Conference Correspondent

The phase 1 EXPLORER and phase 2 PATHFINDER studies demonstrate the efficacy of avapritinib in the treatment of advanced systemic mastocytosis (AdvSM). Avapritinib, a KIT D816V inhibitor, was recently approved to treat AdvSM, which can be divided into 3 subtypes: aggressive SM, SM with an associated hematologic neoplasm (SM-AHN), and mast leukemia. KIT D816V mutations have been identified in 95% of all patients diagnosed with SM, and these genetic alterations are considered to be the primary driver of most mast-cell neoplasms. However, the precise role of KIT D816V mutations in SM-AHN remains unclear, and, in some cases, treatment outcomes remain poor, despite patients having ≥1 KIT D816V mutations. Results from EXPLORER reported here suggest treatment with avapritinib effectively maintains control of AdvSM disease course, regardless of disease subtype, previous treatment, or presence of co-mutations associated with high risk.

Of the 69 patients enrolled in the study, 93% had KIT D816V mutations, 3% had KIT D816Y, and 52% had high-risk SRSF2, ASXL1, and RUNX1 (S/A/R) co-mutations in baseline peripheral blood and bone marrow samples. After treatment with avapritinib, a decrease of ≥50% in KIT D816V variant allele fraction was observed in 88% of patients. In peripheral blood samples, KIT D816V became undetectable in peripheral blood after a median of 15.4 months in 43% of patients. Although most patients responded with reduced mast-cell and KIT D816V burden, 20% of patients, most with the SM-AHN component (n = 10), experienced clinical disease progression (acute myeloid leukemia [n = 6], worse AHN [n = 4], SM progression [n = 2], and undetermined conditions [n = 2]) with median follow-up of 23 months. Progressive disease (83%) was not associated with the KIT D816V allele. There was no consistent pattern of emergent mutations, but 8 patients with disease progression had more S/A/R mutations at baseline (median, 6; range, 3-9) and overall (median, 8; range, 3-12) compared with those without clinical progression (baseline: median, 4 S/A/R co-mutations; overall: median, 4 S/A/R co-mutations).

EXPLORER data indicate promising disease control in patients treated with avapritinib, regardless of mutational status. In addition, avapritinib demonstrates capacity to control AdvSM in patients whose KIT D816V mutations are minimal and who exhibit low clinical progression. However, patients with the AHN component were associated with greater S/A/R baseline and overall co-mutations and disease progression. Additional specific AHN-directed treatment regimens in combination with avapritinib may be necessary to manage patients with the SM-AHN subtype and multiple KIT D816V mutations, and further investigation is needed.

Deininger MW, DeAngelo DJ, Ra DH, et al. Effective control of advance systemic mastocytosis with avapritinib: mutational analysis from the Explorer clinical study. 2021 American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 318.

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