Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study
Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study
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DOI：
10.1016/s1470-2045(18)30649-1
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发表时间：
2018-12-01
期刊：
影响因子：
51.1
通讯作者：
Shaw, Alice T.
中科院分区：
文献类型：
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作者：
Solomon, Benjamin J.;Besse, Benjamin;Shaw, Alice T.
背景洛拉替尼是一种有效的、脑穿透性的第三代ALK和ROS1酪氨酸激酶抑制剂，具有广泛的ALK突变。在1期研究中，在ALK阳性的非小细胞肺癌患者中观察到了活性，他们中的大多数在ALK指导治疗后出现了中枢神经系统转移和进展。我们的目的是分析劳拉替尼在ALK阳性的晚期非小细胞肺癌患者中的整体和颅内抗肿瘤活性。方法在这项2期研究中，组织学或细胞学ALK阳性或ROS1阳性的晚期非小细胞肺癌患者，有或没有中枢神经系统转移，东方合作肿瘤组表现状态为0，1或2，且终末器官功能良好的患者符合条件。根据ALK和ROS1状态和既往治疗情况，患者被纳入6个不同的扩展队列(EXP1-6)，给予劳拉替尼100 mg，每日1次，连续21天为一个周期。主要终点是在ALK阳性患者的集合亚组中评估的独立中心回顾的总体和颅内肿瘤反应。活动和安全性的分析基于独立的中央审查评估的安全性分析集(即，接受至少一剂劳拉替尼的所有患者)。通过独立中心回顾，基线可测量到中枢神经系统转移的患者被纳入颅内活动分析。在这份报告中，我们提供了ALK阳性患者的劳拉替尼活性数据(仅限于EXP1-5)，以及所有接受治疗的患者的安全性数据(EXP1-6)。在2015年9月15日至2016年10月3日期间，276名患者入选：30名ALK阳性且未接受治疗的患者(EXP1)；59名ALK阳性且之前未接受过化疗(n=27；EXP2)或(n=32；EXP3A)的ALK阳性患者；28名ALK阳性且曾接受或未接受化疗(EXP3B)的ALK阳性患者；112名ALK阳性患者，接受过两种(n=66；EXP4)或三种(n=46；EXP5)ALK酪氨酸激酶抑制剂化疗；ROS1阳性者47例(EXP6)。EXP4中有一名患者在接受劳拉替尼治疗前死亡，并被排除在安全性分析集之外。在初治患者(EXP1)中，30例患者中有27例(90.0%；95%可信区间73.5-97.9)达到了客观有效。根据独立的中心回顾，EXP1中有3名患者有可测量的基线中枢神经系统损害，2名患者观察到客观的颅内反应(66.7%；95%可信区间9.4-99.2)。在至少有一种ALK酪氨酸激酶抑制剂(EXP2-5)的ALK阳性患者中，198例患者中有93例(47.0%；39.9-54.2)获得了客观反应，81例患者中，有51例(63.0%；51.5-73.4)有可测量的基线中枢神经系统病变的客观颅内反应。客观有效率分别为69.5%(95%CI 56.1~80.8)、32.1%(9/28)和38.7%(29.6~48.5)。目的：在EXP2-3A可测量基线中枢神经系统病变的23例患者中，20例(87.0%；9.5%可信区间66.4-97.2)有颅内反应；在EXP3B的9例患者中，有5例(55.6%；21.2-86.3)有颅内反应；所有患者中最常见的与治疗相关的不良事件是高胆固醇血症(275名患者中224名[81%]，3-4级患者43名[16%])和高甘油三酯血症(166名患者[60%]，3-4级患者43[16%])。275名患者中有19名(7%)发生了与治疗相关的严重不良事件，7名患者(3%)因与治疗相关的不良事件而永久停止治疗。没有与治疗相关的死亡报告。解释与其广泛的ALK突变覆盖和中枢神经系统渗透一致，劳拉替尼在ALK阳性的非小细胞肺癌治疗初期患者，以及在克里佐替尼(第二代ALK酪氨酸激酶抑制剂)取得进展的患者中，或在多达三种ALK酪氨酸激酶抑制剂之后，都显示出显著的整体和颅内活性。因此，劳拉替尼可能是ALK阳性非小细胞肺癌患者一线或后续治疗的有效治疗选择。版权所有(C)2018爱思唯尔有限公司。保留所有权利。
Background Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a phase 1 study, activity was seen in patients with ALK-positive non-small-cell lung cancer, most of whom had CNS metastases and progression after ALK-directed therapy. We aimed to analyse the overall and intracranial antitumour activity of lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer.Methods In this phase 2 study, patients with histologically or cytologically ALK-positive or ROS1-positive, advanced, non-small-cell lung cancer, with or without CNS metastases, with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and adequate end-organ function were eligible. Patients were enrolled into six different expansion cohorts (EXP1-6) on the basis of ALK and ROS1 status and previous therapy, and were given lorlatinib 100 mg orally once daily continuously in 21-day cycles. The primary endpoint was overall and intracranial tumour response by independent central review, assessed in pooled subgroups of ALK-positive patients. Analyses of activity and safety were based on the safety analysis set (ie, all patients who received at least one dose of lorlatinib) as assessed by independent central review. Patients with measurable CNS metastases at baseline by independent central review were included in the intracranial activity analyses. In this report, we present lorlatinib activity data for the ALK-positive patients (EXP1-5 only), and safety data for all treated patients (EXP1-6). This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865.Findings Between Sept 15, 2015, and Oct 3, 2016, 276 patients were enrolled: 30 who were ALK positive and treatment naive (EXP1); 59 who were ALK positive and received previous crizotinib without (n=27; EXP2) or with (n=32; EXP3A) previous chemotherapy; 28 who were ALK positive and received one previous non-crizotinib ALK tyrosine kinase inhibitor, with or without chemotherapy (EXP3B); 112 who were ALK positive with two (n=66; EXP4) or three (n=46; EXP5) previous ALK tyrosine kinase inhibitors with or without chemotherapy; and 47 who were ROS1 positive with any previous treatment (EXP6). One patient in EXP4 died before receiving lorlatinib and was excluded from the safety analysis set. In treatment-naive patients (EXP1), an objective response was achieved in 27 (90.0%; 95% CI 73.5-97.9) of 30 patients. Three patients in EXP1 had measurable baseline CNS lesions per independent central review, and objective intracranial responses were observed in two (66.7%; 95% CI 9.4-99.2). In ALK-positive patients with at least one previous ALK tyrosine kinase inhibitor (EXP2-5), objective responses were achieved in 93 (47.0%; 39.9-54.2) of 198 patients and objective intracranial response in those with measurable baseline CNS lesions in 51 (63.0%; 51.5-73.4) of 81 patients. Objective response was achieved in 41 (69.5%; 95% CI 56.1-80.8) of 59 patients who had only received previous crizotinib (EXP2-3A), nine (32.1%; 15.9-52.4) of 28 patients with one previous non-crizotinib ALK tyrosine kinase inhibitor (EXP3B), and 43 (38.7%; 29.6-48.5) of 111 patients with two or more previous ALK tyrosine kinase inhibitors (EXP4-5). Objective intracranial response was achieved in 20 (87.0%; 9 5% CI 66.4-97.2) of 23 patients with measurable baseline CNS lesions in EXP2-3A, five (55.6%; 21.2-86.3) of nine patients in EXP3B, and 26 (53.1%; 38.3-67.5) of 49 patients in EXP4-5. The most common treatment-related adverse events across all patients were hypercholesterolaemia (224 [81%] of 275 patients overall and 43 [16%] grade 3-4) and hypertriglyceridaemia (166 [60%] overall and 43 [16%] grade 3-4). Serious treatment-related adverse events occurred in 19 (7%) of 275 patients and seven patients (3%) permanently discontinued treatment because of treatment-related adverse events. No treatment-related deaths were reported.Interpretation Consistent with its broad ALK mutational coverage and CNS penetration, lorlatinib showed substantial overall and intracranial activity both in treatment-naive patients with ALK-positive non-small-cell lung cancer, and in those who had progressed on crizotinib, second-generation ALK tyrosine kinase inhibitors, or after up to three previous ALK tyrosine kinase inhibitors. Thus, lorlatinib could represent an effective treatment option for patients with ALK-positive non-small-cell lung cancer in first-line or subsequent therapy. Copyright (c) 2018 Elsevier Ltd. All rights reserved.