Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials
Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials
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DOI：
10.1016/s1470-2045(19)30691-6
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发表时间：
2020-02-01
期刊：
影响因子：
51.1
通讯作者：
Demetri, George D.
中科院分区：
文献类型：
--
作者：
Doebele, Robert C.;Drilon, Alexander;Demetri, George D.
背景 Entrectinib 是原肌球蛋白受体激酶 (TRK) A、B 和 C 的有效抑制剂，已被证明对 NTRK 基因融合阳性实体瘤具有抗肿瘤活性，包括由于其穿透血脑屏障的能力而具有中枢神经系统活性。我们对三项正在进行的早期试验中携带致癌 NTRK1、NTRK2 和 NTRK3 基因融合的转移性或局部晚期实体瘤患者进行了综合疗效和安全性分析。方法一个综合数据库包含三项正在进行的 1 期或 2 期临床试验（ALKA-372-001、STARTRK-1 和 STARTRK-2）的关键数据集，这些试验纳入了 18 岁或以上的转移性或局部晚期 NTRK 患者融合阳性实体瘤接受恩曲替尼胶囊口服，剂量至少为 600 毫克，每天一次。所有患者的东部肿瘤合作组表现状态均为 0-2，并且可能已接受过既往抗癌治疗（既往 TRK 抑制剂除外）。主要终点，即具有客观缓解的患者比例和中位缓解持续时间，通过在可评估疗效的人群（即未接受过 TRK 抑制剂且已接受至少一剂恩曲替尼的 NTRK 融合阳性实体瘤患者）中进行盲法独立中央审查来评估。总体安全性可评估人群包括来自 STARTRK-1、STARTRK-2、ALKA-372-001 和 STARTRK-NG 的患者（NCT02650401；治疗年轻成人和儿童患者 [年龄]
Background Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood-brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials.Methods An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0-2 and could have received previous anticancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients [aged