Avapritinib Improved Skin Findings in Patients With Indolent Systemic Mastocytosis (ISM) in the Registrational, Double-Blind, Placebo Controlled PIONEER Study

Summary: Background: ISM, characterized by mast cell (MC) accumulation driven by D816V-mutant KIT, can be associated with debilitating symptoms including skin lesions. Skin findings, including MC burden and immunophenotype, were characterized in patients with ISM treated with avapritinib, a selective KIT D816V inhibitor, vs placebo in PIONEER Part 2 (NCT03731260). Methods: Objectives included change from baseline to 24 weeks in spot symptom and skin domain on ISM-Symptom Assessment Form (©2018), a validated patient-reported outcome tool specifically developed to evaluate the severity of symptoms of ISM, as well as skin lesions by photography, and MC number and immunophenotype (CD25+/CD30+) in skin biopsies assessed via light microscopy and immunohistochemistry. Results: In total, 212 patients with ISM received best supportive care plus avapritinib 25 mg once daily (n=141) or placebo (n=71). Mean (standard deviation [SD]) change in spot severity was significantly greater with avapritinib at 24 weeks (−1.86 [2.24]) vs placebo (−0.63 [1.48]; P<0.0001), as was skin symptom domain (−5.87 [6.49] vs −2.64 [4.11]; P<0.0001). Skin domain and mastocytosis Quality of Life Questionnaire improvements were correlated (R=0.578; P<0.0001). In patients with paired photographs, mean percent reduction (SD) in lesion surface area was −37% (53) with avapritinib vs −2% (14) with placebo in the most affected skin region; 86% vs 0% had lightened skin lesion color. Mean (SD) percent change in MC burden decreased at 24 weeks with avapritinib (−22% [106], n=87), but increased with placebo (10% [121], n=49). Avapritinib significantly decreased CD30+ MC proportion in skin lesions at 24 weeks vs placebo (−14% vs −0.47%; P=0.0015). Conclusion: Avapritinib-treated patients with ISM experienced marked reductions in skin symptoms, skin lesion area, and MC burden; an organ target that has not been addressed before. These findings suggest avapritinib treatment may lead to disease modification for skin symptoms.