Avapritinib in Patients With Advanced Gastrointestinal Stromal Tumors Following at Least Three Prior Lines of Therapy.
Avapritinib in Patients With Advanced Gastrointestinal Stromal Tumors Following at Least Three Prior Lines of Therapy.
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DOI：
10.1002/onco.13674
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
von Mehren M
中科院分区：
文献类型：
--
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
大多数由KIT或血小板衍生生长因子受体A（PDGFRA）突变驱动的胃肠道间质瘤（GIST）对可用的酪氨酸激酶抑制剂（TKI）治疗产生耐药性。NAVIGATOR是一项两部分、单组、剂量递增和扩展研究，旨在评价avapritinib（一种选择性强效KIT和PDGFRA抑制剂）在不可切除或转移性GIST患者中的安全性和抗肿瘤活性。合格患者为18岁或以上，经组织学或细胞学证实不可切除的GIST，东部肿瘤协作组体能状态≤2，并开始avapritinib 300 mg或400 mg每日一次治疗。主要终点为开始avapritinib 300 mg或400 mg每日一次治疗的患者的安全性，以及既往接受过3线或3线以上TKI治疗的安全性人群患者的总缓解率（ORR）。截至2018年11月16日，在安全性人群（n = 204）中，最常见的不良事件（AE）为恶心（131 [64%]），疲劳（113 [55%]），贫血（102 [50%]），认知影响（84 [41%]）和眶周水肿（83例[41%]）; 17例（8%）患者因治疗相关AE停药，最常见的是意识模糊、脑病和疲乏。携带KIT或非D842 V PDGFRA突变的GIST且既往至少接受过3种治疗的缓解可评价患者（n = 103）的ORR为17%（95%置信区间[CI]，10-25）。中位缓解持续时间为10.2个月（95% CI，7.2-10.2），中位无进展生存期为3.7个月（95% CI，2.8-4.6）。Avapritinib具有可管理的毒性，在一些具有KIT或PDGFRA突变的GIST患者中作为四线或后续治疗具有有意义的临床活性。在NAVIGATOR试验中，Avapritinib（一种KIT和血小板源性生长因子受体A酪氨酸激酶抑制剂）在部分既往接受过3种或3种以上治疗的晚期胃肠道间质瘤（GIST）患者中提供了持久缓解。Avapritinib具有可耐受的安全性特征，在大多数情况下，认知不良事件可通过剂量中断和调整进行管理。这些结果表明，avapritinib可以在一些接受过大量预治疗的GIST患者中引起持久的治疗反应，这些患者的治疗选择有限。本文介绍了avapritinib在转移性或不可切除的KIT或PDGFRA突变型胃肠道间质瘤患者中的I期NAVIGATOR试验的安全性和疗效结果，疗效分析重点关注既往接受过至少三线治疗的患者。
Most gastrointestinal stromal tumors (GIST) driven by KIT or platelet‐derived growth factor receptor A (PDGFRA) mutations develop resistance to available tyrosine kinase inhibitor (TKI) treatments. NAVIGATOR is a two‐part, single‐arm, dose escalation and expansion study designed to evaluate safety and antineoplastic activity of avapritinib, a selective, potent inhibitor of KIT and PDGFRA, in patients with unresectable or metastatic GIST. Eligible patients were 18 years or older with histologically or cytologically confirmed unresectable GIST and Eastern Cooperative Oncology Group performance status ≤2 and initiated avapritinib at 300 mg or 400 mg once daily. Primary endpoints were safety in patients who initiated avapritinib at 300 mg or 400 mg once daily and overall response rate (ORR) in patients in the safety population with three or more previous lines of TKI therapy. As of November 16, 2018, in the safety population (n = 204), the most common adverse events (AEs) were nausea (131 [64%]), fatigue (113 [55%]), anemia (102 [50%]), cognitive effects (84 [41%]), and periorbital edema (83 [41%]); 17 (8%) patients discontinued due to treatment‐related AEs, most frequently confusion, encephalopathy, and fatigue. ORR in response‐evaluable patients with GIST harboring KIT or non‐D842V PDGFRA mutations and with at least three prior therapies (n = 103) was 17% (95% confidence interval [CI], 10–25). Median duration of response was 10.2 months (95% CI, 7.2–10.2), and median progression‐free survival was 3.7 months (95% CI, 2.8–4.6). Avapritinib has manageable toxicity with meaningful clinical activity as fourth‐line or later treatment in some patients with GIST with KIT or PDGFRA mutations. In the NAVIGATOR trial, avapritinib, an inhibitor of KIT and platelet‐derived growth factor receptor A tyrosine kinases, provided durable responses in a proportion of patients with advanced gastrointestinal stromal tumors (GIST) who had received three or more prior therapies. Avapritinib had a tolerable safety profile, with cognitive adverse events manageable with dose interruptions and modification in most cases. These findings indicate that avapritinib can elicit durable treatment responses in some patients with heavily pretreated GIST, for whom limited treatment options exist. This article presents safety and efficacy findings of the phase I NAVIGATOR trial of avapritinib in patients with metastatic or unresectable KIT‐ or PDGFRA‐ mutant gastrointestinal stromal tumors with the efficacy analysis focused on patients who had previously received a minimum of three prior lines of therapy.
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DOI：
10.1002/onco.13632
发表时间：
2021-04
期刊：
The oncologist
影响因子：
--
作者：
Joseph CP;Abaricia SN;Angelis MA;Polson K;Jones RL;Kang YK;Riedel RF;Schöffski P;Serrano C;Trent J;Tetzlaff ED;Si TD;Zhou T;Doyle A;Bauer S;Roche M;Havnaer T
通讯作者：
Havnaer T
影响因子：
45.3
作者：
Choi, Haesun;Charnsangavej, Chuslip;Benjamin, Robert S.
通讯作者：
Benjamin, Robert S.
影响因子：
45.3
作者：
Blanke, Charles D.;Rankin, Cathryn;Borden, Ernest C.
通讯作者：
Borden, Ernest C.
DOI：
10.1073/pnas.0812413106
发表时间：
2009-02-03
影响因子：
11.1
作者：
Gajiwala, Ketan S.;Wu, Joe C.;Demetri, George D.
通讯作者：
Demetri, George D.
影响因子：
50.5
作者：
Ben-Ami, E.;Barysauskas, C. M.;George, S.
通讯作者：
George, S.