Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial
Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial
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DOI：
10.1016/s1470-2045(20)30269-2
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发表时间：
2020-07-01
期刊：
影响因子：
51.1
通讯作者：
George, Suzanne
中科院分区：
文献类型：
--
作者：
Heinrich, Michael C.;Jones, Robin L.;George, Suzanne
伊马替尼靶向KIT和PDGFRA彻底改变了胃肠道间质瘤的治疗；然而，PDGFRA Asp842Val （D842V）突变的胃肠道间质瘤对酪氨酸激酶抑制剂具有高度耐药性。我们旨在评估avapritinib的安全性、耐受性和抗肿瘤活性，avapritinib是一种新型KIT和PDGFRA抑制剂，可有效抑制PDGFRA D842V，用于晚期胃肠道间质肿瘤患者，包括KIT和PDGFRA D842V突变的胃肠道间质肿瘤（NAVIGATOR）患者。NAVIGATOR是一项两部分、开放标签、剂量递增和剂量扩展的i期研究，在9个国家（比利时、法国、德国、波兰、荷兰、韩国、西班牙、英国和美国）的17个地点进行。年龄在18岁及以上、Eastern Cooperative Oncology Group评分为2分及以下、终末器官功能良好的患者均有资格参加。该研究的剂量递增部分包括无法切除的胃肠道间质肿瘤患者。该研究的剂量扩大部分包括不可切除的PDGFRA d842v突变胃肠道间质瘤患者，无论先前是否接受过治疗，或具有其他突变的胃肠道间质瘤，这些患者要么在伊马替尼和一种或多种酪氨酸激酶抑制剂治疗下进展，要么以前只接受过伊马替尼治疗。基于入组趋势、对研究数据的持续审查以及对胃肠道间质瘤治疗模式的不断发展的认识，由申办者的医学主任与研究人员共同决定，PDGFRA D842V突变患者将被单独分析；本文报道了这组患者的结果。剂量递增部分每日口服阿伐替尼1次（起始剂量为30mg，逐渐增加剂量水平，每日1次，连续28天周期，直到确定最大耐受剂量或推荐的2期剂量；在剂量递增部分，起始剂量为剂量递增部分的最大耐受剂量）。主要终点是最大耐受剂量、推荐的2期剂量和剂量递增部分的安全性，以及剂量递增部分的总体反应和安全性。对剂量递增部分的所有患者和剂量扩展部分的所有PDGFRA d842v突变型胃肠道间质瘤患者进行安全性评估，并对接受阿伐替尼治疗的所有PDGFRA d842v突变型胃肠道间质瘤患者进行活性评估，这些患者至少有一个靶病变和至少一个基线后放射学疾病评估。本研究已在ClinicalTrials.gov注册，编号NCT02508532。2015年10月26日至2018年11月16日（数据截止），46例患者入组剂量递增部分，其中20例PDGFRA d842v突变型胃肠道间质瘤患者入组剂量递增部分，36例PDGFRA d842v突变型胃肠道间质瘤患者入组剂量递增部分。截至数据截止日期（2018年11月16日），82例安全人群中有38例（46%）患者（中位随访19.1个月[IQR 9.2-25.5]）， 56例PDGFRA D842V人群中有37例（66%）患者（中位随访15.9个月[IQR 9]）。2-24。[9])仍在接受治疗。最大耐受剂量为400毫克，推荐的2期剂量为300毫克。在安全人群（来自剂量递增和剂量扩展部分的PDGFRA d842v突变胃肠道间质瘤患者，所有剂量）中，82例患者中有47例（57%）发生与治疗相关的3-4级事件，最常见的是贫血（14例[17%]）；没有与治疗相关的死亡。在PDGFRA d842v突变人群中，56例患者中有49例（88%;95% CI 76-95）有总体缓解，5例（9%）完全缓解，44例（79%）部分缓解。每天30-400毫克剂量未观察到剂量限制性毒性。服用600mg时，两名患者出现剂量限制性毒性（患者1为2级高血压、痤疮样皮炎和记忆障碍，患者2为2级高胆红素血症）。Avapritinib具有可管理的安全性，并且在晚期PDGFRA d842v突变的胃肠道间质肿瘤患者中具有初步的抗肿瘤活性。爱思唯尔版权所有版权所有。
Background Targeting of KIT and PDGFRA with imatinib revolutionised treatment in gastrointestinal stromal tumour; however, PDGFRA Asp842Val (D842V)-mutated gastrointestinal stromal tumour is highly resistant to tyrosine kinase inhibitors. We aimed to assess the safety, tolerability, and antitumour activity of avapritinib, a novel KIT and PDGFRA inhibitor that potently inhibits PDGFRA D842V, in patients with advanced gastrointestinal stromal tumours, including patients with KIT and PDGFRA D842V-mutant gastrointestinal stromal tumours (NAVIGATOR).Methods NAVIGATOR is a two-part, open-label, dose-escalation and dose-expansion, phase 1 study done at 17 sites across nine countries (Belgium, France, Germany, Poland, Netherlands, South Korea, Spain, the UK, and the USA). Patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 2 or less, and with adequate end-organ function were eligible to participate. The dose-escalation part of the study included patients with unresectable gastrointestinal stromal tumours. The dose-expansion part of the study included patients with an unresectable PDGFRA D842V-mutant gastrointestinal stromal tumour regardless of previous therapy or gastrointestinal stromal tumour with other mutations that either progressed on imatinib and one or more tyrosine kinase inhibitor, or only received imatinib previously. On the basis of enrolment trends, ongoing review of study data, and evolving knowledge regarding the gastrointestinal stromal tumour treatment paradigm, it was decided by the sponsor's medical director together with the investigators that patients with PDGFRA D842V mutations would be analysed separately; the results from this group of patients is reported in this Article. Oral avapritinib was administered once daily in the dose-escalation part (starting dose of 30 mg, with increasing dose levels once daily in continuous 28-day cycles until the maximum tolerated dose or recommended phase 2 dose was determined; in the dose-expansion part, the starting dose was the maximum tolerated dose from the dose-escalation part). Primary endpoints were maximum tolerated dose, recommended phase 2 dose, and safety in the dose-escalation part, and overall response and safety in the dose-expansion part. Safety was assessed in all patients from the dose-escalation part and all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour in the dose-expansion part, and activity was assessed in all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour who received avapritinib and who had at least one target lesion and at least one post-baseline disease assessment by central radiology. This study is registered with ClinicalTrials.gov, NCT02508532.Findings Between Oct 26, 2015, and Nov 16, 2018 (data cutoff), 46 patients were enrolled in the dose-escalation part, including 20 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour, and 36 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour were enrolled in the dose-expansion part. At data cutoff (Nov 16, 2018), 38 (46%) of 82 patients in the safety population (median follow-up of 19.1 months [IQR 9.2-25.5]) and 37 (66%) of the 56 patients in the PDGFRA D842V population (median follow-up of 15.9 months [IQR 9. 2-24. 9]) remained on treatment. The maximum tolerated dose was 400 mg, and the recommended phase 2 dose was 300 mg. In the safety population (patients with PDGFRA D842V-mutant gastrointestinal stromal tumour from the doseescalation and dose-expansion parts, all doses), treatment-related grade 3-4 events occurred in 47 (57%) of 82 patients, the most common being anaemia (14 [17%]); there were no treatment-related deaths. In the PDGFRA D842V-mutant population, 49 (88%; 95% CI 76-95) of 56 patients had an overall response, with five (9%) complete responses and 44 (79%) partial responses. No dose-limiting toxicities were observed at doses of 30-400 mg per day. At 600 mg, two patients had dose-limiting toxicities (grade 2 hypertension, dermatitis acneiform, and memory impairment in patient 1, and grade 2 hyperbilirubinaemia in patient 2).Interpretation Avapritinib has a manageable safety profile and has preliminary antitumour activity in patients with advanced PDGFRA D842V-mutant gastrointestinal stromal tumours. Copyright (C) 2020 Elsevier Ltd. All rights reserved.