Division of Hematology, Stanford Cancer Institute/Stanford University School of Medicine, Stanford, CA, USA.
Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany.
Nat Med. 2021 Dec;27(12):2192-2199. doi: 10.1038/s41591-021-01539-8. Epub 2021 Dec 6.
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), 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.
高级系统性肥大细胞增多症（AdvSM）是一种罕见的、KIT D816V 驱动的血液恶性肿瘤，其特征为肥大细胞浸润和生存时间缩短。我们报告了正在进行的一项关键性单臂 2 期试验（编号：NCT03580655）的中期分析结果，该试验评估了 avapritinib 在 AdvSM 患者中的疗效，avapritinib 是一种有效的、选择性的 KIT D816V 抑制剂，主要以每日一次 200mg 的起始剂量给药（n=62）。主要终点是总体缓解率（ORR）。次要终点包括 AdvSM-症状评估表单总症状评分和生活质量的基线平均变化、反应时间、反应持续时间、无进展生存期、总生存期、疾病负担和安全性的测量变化。主要终点成功达到（P=1.6×10），在 32 名可评估反应的 AdvSM 患者中，ORR 为 75%（95%置信区间 57-89），其中包括 19%的完全缓解患者，具有完全或部分血液学恢复。观察到血清类胰蛋白酶（93%）、骨髓肥大细胞（88%）和 KIT D816V 变异等位基因分数（60%）从基线降低≥50%。最常见的≥3 级不良事件是中性粒细胞减少症（24%）、血小板减少症（16%）和贫血（16%）。Avapritinib 在 AdvSM 患者中显示出较高的临床、形态学和分子缓解率，且总体耐受性良好。
