Reductions in Indolent Systemic Mastocytosis Biomarker Burden With Avapritinib in the Registrational, Double-Blind, Placebo-Controlled PIONEER Trial

Topic: 16. Myeloproliferative neoplasms - Clinical Background: Indolent systemic mastocytosis (ISM), a clonal mast cell (MC) disease primarily driven by the KIT D816V mutation, is characterized by abnormal MC accumulation and activation. To date, no therapies have demonstrated disease modification in a controlled trial. PIONEER (NCT03731260) is a randomized, double-blind, placebo-controlled study of avapritinib, a potent, highly selective, oral inhibitor of KIT D816V in patients with symptomatic ISM despite best supportive care (BSC). Recently reported findings (Castells M, et al. J Allergy Clin Immunol. 2023;151(2):AB204) from this trial demonstrated that patients treated with avapritinib achieved significantly greater improvement in patient-reported total symptom scores (TSS) vs placebo after 24 weeks of treatment. Aims: To assess the impact of avapritinib vs placebo on objective biomarkers of MC burden in patients with ISM. Methods: Adult patients with ISM were randomly assigned 2:1 to avapritinib 25 mg QD + BSC (“avapritinib”) or placebo + BSC (“placebo”) groups and stratified by baseline serum tryptase (<20 ng/mL vs ≥20 ng/mL). Endpoints included ≥50% reduction in serum tryptase, bone marrow (BM) MC burden, and KIT D816V variant allele frequency (VAF) in peripheral blood (PB) at 24 weeks. One-sided P-values are reported. Additional analyses included reduction of serum tryptase to <20 ng/mL, total clearance of BM MC aggregates, and reduction of KIT D816V VAF to undetectable levels (<0.02%). Patient-reported outcomes included TSS evaluated using the ISM symptom assessment form (ISM-SAF ©2018). Safety was also assessed. Results: Baseline characteristics for patients in the avapritinib (n=141) and placebo (n=71) groups were similar. In the avapritinib group, baseline median (range) serum tryptase, BM MC burden, and KIT D816V VAF in PB were 38.4 ng/mL (3.6–256.0), 7.0% (1.0–50.0), and 0.4% (0.02–41.3), and in the placebo group were 43.7 ng/mL (5.7–501.6), 7.0% (1.0–70.0), and 0.3% (0.02–36.7). At week 24, a significantly greater proportion of patients in the avapritinib group vs placebo group (all P<0.0001) achieved ≥50% reductions in serum tryptase levels (54% [76/141] vs 0% [0/71]), BM MC burden (53% [56/106] vs 23% [13/57]), and KIT D816V VAF (68% [80/118] vs 6% [4/63]). Reduction of serum tryptase to <20 ng/mL from ≥20 ng/mL at baseline was observed in 54% (58/107; <11.4 ng/mL, n=29; 11.4–<20 ng/mL, n=29) in the avapritinib group vs 2% (11.4–<20 ng/mL, n=1/50) in the placebo group. Mean percent change (SD) BM MC burden was greater with avapritinib vs placebo (–11.3% [84.1] vs 0.4% [69.1]). Of patients with BM MC aggregates at baseline, total clearance of BM MC aggregates was three times more common in the avapritinib group than placebo (36% [n=33/91] vs 12% [n=6/50]). Of patients with detectable KIT D816V VAF at baseline, 11% (n=12/109) in the avapritinib group had undetectable KIT D816V VAF at 24 weeks vs 6% (n=3/54) in the placebo group. In the primary endpoint analysis, the avapritinib group had significantly greater mean change (95% CI) in TSS at 24 weeks vs placebo (–15.6 [–18.6, –12.6] vs –9.2 [–13.1, –5.2]; P=0.003). Avapritinib was well tolerated with a safety profile comparable to placebo. Summary/Conclusion: In patients with ISM, avapritinib 25 mg QD significantly reduced objective biomarkers of MC burden, notably improved symptoms, and was well-tolerated. These results support avapritinib as a potentially disease-modifying therapy for patients with ISM.Keywords: c-kit, Systemic mastocytosis, Tyrosine kinase inhibitor