Avapritinib improved gastrointestinal symptoms in patients with indolent systemic mastocytosis: registrational double-blind, placebo-controlled pioneer study

IntroductionIndolent systemic mastocytosis (ISM), a clonal mast-cell disease primarily driven by the KIT D816V mutation, can cause lifelong debilitating symptoms across multiple organ systems. Gastrointestinal (GI) symptoms are frequently reported in patients with ISM, negatively impacting their quality of life. PIONEER (NCT03731260) demonstrated that avapritinib, a highly selective KIT D816V inhibitor, significantly improved total symptom scores (TSS) and reduced objective measures of mast-cell burden versus placebo.MethodsPatients with moderate to severe ISM (TSS ≥28) were randomized 2:1 to 25 mg avapritinib once daily (n=141) or placebo (n=71), both with best supportive care (BSC). Mean change in TSS (range 0–110) was based on a 14-day average of patient-reported severity of 11 ISM symptoms (0=none; 10=worst imaginable) on the ISM-Symptom Assessment Form (ISM-SAF; ©2018 Blueprint Medicines Corporation).ResultsPer ISM-SAF, patients experienced better improvements in GI symptoms at Week 24 with avapritinib versus placebo (abdominal pain, –38.2 vs –14.6; diarrhea severity, –32.0 vs –21.7; nausea, –26.4 vs –14.9). Patients with ≥30% and ≥50% reduction in TSS showed improvement from baseline in diarrhea count (–59% and –65%), and rapid and sustained improvements in abdominal pain (–70% and –85%), diarrhea severity (–65% and –71%), and nausea (–75% and –88%) (Figure). With avapritinib, patients were more likely to decrease/discontinue use of BSC medications, including cromolyn. Adverse events (AEs) were similar and serious AEs were lower with avapritinib versus placebo.ConclusionAvapritinib improved all individual symptoms, notably improved ISM GI symptoms, and was well-tolerated. Results support avapritinib as a promising new treatment for ISM.