IntroductionAdvanced systemic mastocytosis (AdvSM), which includes aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL), is a clonal hematologic neoplasm predominantly driven by the KIT D816V mutation. It is characterized by the proliferation and infiltration of neoplastic mast cells (MCs), and, variably, hematologic (usually myeloid) neoplasms, resulting in organ damage and reduced survival. Approximately 50% of patients with AdvSM exhibit skin lesions of mastocytosis adding to the impaired quality of life of patients. Avapritinib is an oral, potent, selective inhibitor of KIT D816V approved in the United States, regardless of prior therapy, and in the European Union (EU), after ≥1 prior therapy, for adults with AdvSM. Here, we present the effects of avapritinib on skin lesions in patients with AdvSM enrolled in the phase 2 PATHFINDER study (NCT03580655).

Methods

All patients initiated 200 mg avapritinib once daily. Skin images of 4 views (front torso, back torso, front thigh, and back thigh) were captured by photography at 5 timepoints: Screening, Week 8, Week 24, Week 40, and Week 64. Four computer vision artificial intelligence algorithms were developed at Canfield Scientific, creating target area of interest (AOI) metrics: area of the AOI, area of detected mastocytosis skin lesions, percent of AOI with detected mastocytosis skin lesions (fractional area), and detected lesion count. Four independent dermatologists evaluated images for the appropriate computer algorithms in a blinded setting. Patient-reported symptoms in skin were captured using the validated 10-item (0 = “none” and 10 = “worst imaginable”) AdvSM-Symptom Assessment Form (AdvSM-SAF), which assesses symptoms specific to AdvSM over a recall period of 24 h. Overall skin domain scores (sum of individual scores for itching, flushing, and spots; range: 0–30) were generated based on average scores for each 7 days. Mean change in AdvSM-SAF score was assessed using one-sided t-tests. Overall response rate (ORR) was assessed per mIWG-MRT-ECNM criteria by central adjudication and the objective disease burden by bone marrow mast cell (BMMC) percentage, serum tryptase levels, KIT D816V variant allele frequency (VAF) in blood, and spleen volume. Results

Of 107 patients enrolled in PATHFINDER, 34 (32%), including 18 with SM-AHN, 10 with MCL, and 6 with ASM, had baseline and ≥1 evaluable post-baseline skin assessments. Median age (range) was 67 (37–85) years; 71% were male. In this skin assessment patient population, a ≥50% reduction in serum tryptase, KIT D816V VAF, and BMMC burden, and ≥35% reduction in spleen volume, were achieved in 82% (28/34 patients), 71% (24/34), 82% (28/34), and 62% (21/34) of patients, respectively. Notable proportions of patients experienced normalization of these objective disease burden measures, including total clearance of BMMC aggregates in the bone marrow (62%), undetectable KIT D816V VAF (29%), and serum tryptase <20 ng/mL (50%). Median reduction from baseline at Week 64 in fractional area affected by skin lesions for the front torso, back torso, front thigh, and back thigh was 73%, 76%, 50%, and 57%, respectively. Median reduction at Week 64 in the most affected area was 75%. Reductions were rapid and durable; improvements in the most affected area reached 50% at Week 8 and were maintained through Week 64. Change in skin lesion color of the front torso (8/9), back torso (9/9), front thigh (6/8), and back thigh (4/7) by Week 64 was adjudicated to be “lighter” or “a lot lighter”. The most affected body part was adjudicated as “lighter” or “a lot lighter” in 13 of 15 (87%) patients by Week 8 and sustained in 8 of 9 (89%) patients thereafter until Week 64. Mean (standard deviation; number of patients) AdvSM-SAF skin severity score at baseline was 9.6 (6.8; 31) and significantly decreased to 4.8 (3.7; 32) at Week 8, 4.7 (3.4; 31) at Week 24, 4.0 (2.9; 34) at Week 40, and 3.4 (2.9; 32) at Week 64 (all P<0.001). Of the 34 patients with skin assessments, 30 patients were response-evaluable with ORR (95% confidence interval) of 73% (54–88).Conclusion

Avapritinib treatment in patients with AdvSM resulted in rapid reductions in affected skin lesion area and improvement in skin lesion color in the majority of patients that was sustained for more than 1 year. The visible and patient-reported improvement in skin symptoms augment observed, sustained efficacy in this cohort of patients.

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2025
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