Advanced systemic mastocytosis (AdvSM) is a rare, KIT D816V-driven hematologic neoplasm characterized by mast cell infiltration and shortened survival. We report the results of a prespecified interim analysis of an ongoing pivotal single-arm phase 2 trial (no. NCT03580655) of avapritinib, a potent, selective KIT D816V inhibitor administered primarily at a once-daily starting dose of 200 mg in patients with AdvSM (n = 62). The primary endpoint was overall response rate (ORR). Secondary endpoints included mean baseline change in AdvSM–Symptom Assessment Form Total Symptom Score and quality of life, time to response, duration of response, progression-free survival, overall survival, changes in measures of disease burden and safety. The primary endpoint was successfully met (P = 1.6 × 10^-9), with an ORR of 75% (95% confidence interval 57–89) in 32 response-evaluable patients with AdvSM who had sufficient follow-up for response assessment, including 19% with complete remission with full or partial hematologic recovery. Reductions of ≥50% from baseline in serum tryptase (93%), bone marrow mast cells (88%) and KIT D816V variant allele fraction (60%) were observed. The most frequent grade ≥3 adverse events were neutropenia (24%), thrombocytopenia (16%) and anemia (16%). Avapritinib demonstrated a high rate of clinical, morphological and molecular responses and was generally well tolerated in patients with AdvSM.

晚期系统性肥大细胞增多症 (AdvSM) 是一种罕见的KIT D816V 驱动的血液肿瘤，其特征是肥大细胞浸润和生存期缩短。我们报告了对 avapritinib 正在进行的关键单臂 2 期试验（编号 NCT03580655）的预先指定的中期分析结果，avapritinib 是一种强效、选择性 KIT D816V 抑制剂，主要以每日一次 200 mg 的起始剂量在 AdvSM 患者中给药( n  = 62)。主要终点是总体反应率（ORR）。次要终点包括 AdvSM-症状评估表总症状评分的平均基线变化和生活质量、反应时间、反应持续时间、无进展生存期、总生存期、疾病负担和安全性措施的变化。主要终点成功达到（P  = 1.6 × 10 ^-9），在 32 名 AdvSM 反应可评估患者中，ORR 为 75%（95% 置信区间 57-89），这些患者对反应评估进行了充分的随访，其中 19% 完全缓解且完全缓解或部分血液学恢复。观察到血清类胰蛋白酶 (93%)、骨髓肥大细胞 (88%) 和KIT D816V 变异等位基因部分 (60%) 比基线减少 ≥50%。最常见的 3 级以上不良事件是中性粒细胞减少 (24%)、血小板减少 (16%) 和贫血 (16%)。Avapritinib 表现出很高的临床、形态学和分子学反应率，并且在 AdvSM 患者中通常具有良好的耐受性。