Avapritinib achieves long-term disease control with favorable safety in patients with indolent systemic mastocytosis over 3 years

Background: Indolent systemic mastocytosis (ISM), a clonal mast cell disease primarily driven by the KIT D816V mutation, can cause long-term debilitating symptoms and poor quality of life. Most patients rely on symptom-directed best supportive care (BSC) medications, which do not treat the underlying driver of ISM. Avapritinib, an oral, potent, selective KIT D816V inhibitor, is approved in adults with ISM. Objective: We sought to understand the long-term efficacy and safety of avapritinib in ISM. Methods: The PIONEER trial (NCT03731260) enrolled adults with moderate to severe ISM symptoms. Patients initiated avapritinib 25 mg once daily (QD; recommended dose) plus BSC in part 1, 2, or 3; open-label part 3 is ongoing with up to 5 years of follow-up. As per investigator discretion and disease burden, a dose increase up to avapritinib 50 mg QD was permitted in part 3. Results: As of February 21, 2025, 226 patients initiated avapritinib at 25 mg QD. The median (range) treatment duration was 40.0 (0.7-67.2) months. Patients receiving avapritinib experienced durable and clinically meaningful symptom improvement (mean change, −19.39 [n = 127] in the Indolent Systemic Mastocytosis Symptom Assessment Form total symptom score) through approximately 3 years. Avapritinib continued to be well tolerated for a longer term with a safety profile comparable with the previously reported placebo-controlled portion. Most treatment-related adverse events (TRAEs) were grades 1 to 2, with limited grade 3 or higher reported. Edema events were the most frequent TRAEs (mostly grade 1). Serious TRAEs occurred in 3 patients (1%), and 7 patients (3%) discontinued treatment because of TRAEs. Conclusions: Long-term follow-up (median, ∼3 years) demonstrates that avapritinib is effective and well tolerated. Avapritinib shows a favorable benefit-risk profile as a chronic ISM treatment.