Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Royal Marsden Hospital and Institute of Cancer Research, London, UK.
Oncologist. 2021 Apr;26(4):e639-e649. doi: 10.1002/onco.13674. Epub 2021 Feb 1.
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.
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）对现有的酪氨酸激酶抑制剂（TKI）治疗产生耐药性。NAVIGATOR 是一项两部分、单臂、剂量递增和扩展研究，旨在评估 avapritinib（一种选择性、强效的 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。
符合条件的患者为 18 岁或以上，组织学或细胞学证实不可切除的 GIST，东部合作肿瘤学组体能状态≤2，并以 300mg 或 400mg 每日一次起始接受 avapritinib 治疗。主要终点为 300mg 或 400mg 每日一次起始接受 avapritinib 治疗的患者的安全性和既往接受三线或以上 TKI 治疗的安全性人群中反应评估患者的总缓解率（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[41%]）；17（8%）名患者因治疗相关 AE 而停药，最常见的是意识混乱、脑病和疲劳。在既往接受三线或以上治疗的具有 KIT 或非 D842V PDGFRA 突变且至少有三种既往治疗的反应可评估的 GIST 患者（n=103）中，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 作为某些 KIT 或 PDGFRA 突变的 GIST 患者的四线或以上治疗药物，具有可管理的毒性和有意义的临床活性。
在 NAVIGATOR 试验中，avapritinib（一种 KIT 和血小板衍生生长因子受体 A 酪氨酸激酶抑制剂）在接受三种或更多种既往治疗的晚期胃肠道间质瘤（GIST）患者中提供了持久的反应。avapritinib 具有可耐受的安全性特征，大多数情况下认知不良事件可通过剂量中断和调整来管理。这些发现表明，avapritinib 可以在一些接受过多线治疗的 GIST 患者中引发持久的治疗反应，这些患者的治疗选择有限。
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