Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial.
Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial.
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DOI：
10.1038/s41591-021-01538-9
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发表时间：
2021-12
期刊：
影响因子：
82.9
通讯作者：
Gotlib J
中科院分区：
文献类型：
--
作者：
DeAngelo DJ;Radia DH;George TI;Robinson WA;Quiery AT;Drummond MW;Bose P;Hexner EO;Winton EF;Horny HP;Tugnait M;Schmidt-Kittler O;Evans EK;Lin HM;Mar BG;Verstovsek S;Deininger MW;Gotlib J
晚期系统性肥大细胞增多症（AdvSM）是一种罕见的血液肿瘤，由KIT D816 V突变驱动，与生存率低相关。这项I期研究（NCT 02561988）在AdvSM患者中评价了avapritinib（BLU-285），一种选择性KIT D816 V抑制剂。主要终点是avapritinib的最大耐受剂量、推荐的II期剂量和安全性。次要终点包括总体缓解率和肥大细胞负荷指标的变化。在86例患者中评价了Avapritinib 30-400 mg每日一次的剂量，其中69例患者患有中心确认的AdvSM。未达到最大耐受剂量，在剂量扩展队列中研究了每日200 mg和300 mg。最常见的不良事件是眶周水肿（69%）、贫血（55%）、腹泻（45%）、血小板减少症（44%）和恶心（44%）。颅内出血的发生率为13%，但只有1%的患者没有严重的血小板减少症（血小板<50 × 109/l）。在53例缓解可评价患者中，总缓解率为75%。完全缓解率为36%。Avapritinib分别在92%和99%的患者中引起骨髓肥大细胞和血清类胰蛋白酶降低≥50%。Avapritinib诱导了深度和持久的缓解，包括AdvSM患者中KIT D816 V的分子缓解，并且在推荐的II期剂量200 mg每日一次下耐受良好。在晚期系统性肥大细胞增多症患者的I期试验中，avapritinib（一种选择性KIT抑制剂）通常耐受良好，引起持久的临床应答，并导致肥大细胞疾病负荷降低。
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. In a phase 1 trial of patients with advanced systemic mastocytosis, avapritinib, a selective KIT inhibitor, was generally well tolerated, elicited durable clinical responses and led to reductions in mast cell disease burden.
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影响因子：
20.3
作者：
Garcia-Montero, Andres C.;Jara-Acevedo, Maria;Orfao, Alberto
通讯作者：
Orfao, Alberto
影响因子：
3.7
作者：
Hermine, Olivier;Lortholary, Olivier;Leventhal, Phillip S.;Catteau, Adeline;Soppelsa, Frederique;Baude, Cedric;Cohen-Akenine, Annick;Palmerini, Fabienne;Hanssens, Katia;Yang, Ying;Sobol, Hagay;Fraytag, Sylvie;Ghez, David;Suarez, Felipe;Barete, Stephane;Casassus, Philippe;Sans, Beatrice;Arock, Michel;Kinet, Jean Pierre;Dubreuil, Patrice;Moussy, Alain
通讯作者：
Moussy, Alain
DOI：
10.1002/onco.13674
发表时间：
2021-04
期刊：
The oncologist
影响因子：
--
作者：
George S;Jones RL;Bauer S;Kang YK;Schöffski P;Eskens F;Mir O;Cassier PA;Serrano C;Tap WD;Trent J;Rutkowski P;Patel S;Chawla SP;Meiri E;Gordon M;Zhou T;Roche M;Heinrich MC;von Mehren M
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von Mehren M
影响因子：
20.3
作者：
Lim, Ken-Hong;Tefferi, Ayalew;Pardanani, Animesh
通讯作者：
Pardanani, Animesh
影响因子：
51.1
作者：
Heinrich, Michael C.;Jones, Robin L.;George, Suzanne
通讯作者：
George, Suzanne