Advanced systemic mastocytosis (AdvSM) is a rare hematologic neoplasm driven by the KIT D816V mutation and associated with poor survival. This phase 1 study (NCT02561988) evaluated avapritinib (BLU-285), a selective KIT D816V inhibitor, in patients with AdvSM. The primary endpoints were the maximum tolerated dose, recommended phase 2 dose and safety of avapritinib. Secondary endpoints included overall response rate and changes in measures of mast cell burden. Avapritinib was evaluated at doses of 30–400 mg once daily in 86 patients, 69 with centrally confirmed AdvSM. Maximum tolerated dose was not reached, and 200 mg and 300 mg daily were studied in dose-expansion cohorts. The most frequent adverse events observed were periorbital edema (69%), anemia (55%), diarrhea (45%), thrombocytopenia (44%) and nausea (44%). Intracranial bleeding occurred in 13% overall, but in only 1% of patients without severe thrombocytopenia (platelets <50 × 10⁹/l). In 53 response-evaluable patients, the overall response rate was 75%. The complete remission rate was 36%. Avapritinib elicited ≥50% reductions in marrow mast cells and serum tryptase in 92% and 99% of patients, respectively. Avapritinib induced deep and durable responses, including molecular remission of KIT D816V in patients with AdvSM, and was well tolerated at the recommended phase 2 dose of 200 mg daily.

晚期系统性肥大细胞增多症 (AdvSM) 是一种由KIT驱动的罕见血液肿瘤D816V 突变并与较差的生存率相关。这项 1 期研究 (NCT02561988) 在 AdvSM 患者中评估了选择性 KIT D816V 抑制剂 avapritinib (BLU-285)。主要终点是最大耐受剂量、推荐的 2 期剂量和 avapritinib 的安全性。次要终点包括总体反应率和肥大细胞负荷测量值的变化。在 86 名患者中以 30-400 mg 的剂量每天一次对 Avapritinib 进行了评估，其中 69 名患者接受了中央证实的 AdvSM。未达到最大耐受剂量，在剂量扩展队列中研究了每天 200 毫克和 300 毫克。观察到的最常见的不良事件是眶周水肿（69%）、贫血（55%）、腹泻（45%）、血小板减少（44%）和恶心（44%）。总体而言，13% 的患者发生颅内出血，但只有 1% 的患者没有严重的血小板减少症（血小板 <⁹ /升）。在 53 名可评估反应的患者中，总反应率为 75%。完全缓解率为36%。Avapritinib 分别在 92% 和 99% 的患者中引起 ≥50% 的骨髓肥大细胞和血清类胰蛋白酶减少。Avapritinib 在 AdvSM 患者中诱导了深度和持久的反应，包括KIT D816V 的分子缓解，并且在每天 200 mg 的推荐 2 期剂量下具有良好的耐受性。