Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study
Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study
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DOI：
10.1016/s1470-2045(14)70362-6
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发表时间：
2014-09-01
期刊：
影响因子：
51.1
通讯作者：
Ou, Sai-Hong Ignatius
中科院分区：
文献类型：
--
作者：
Gadgeel, Shirish M.;Gandhi, Leena;Ou, Sai-Hong Ignatius
背景：非小细胞肺癌（NSCLC）和ALK重排患者在接受ALK抑制剂克唑替尼治疗时，通常有8-11个月的无进展生存期。然而，抵抗不可避免地出现，大脑是一个常见的进展部位。迫切需要更有效的ALK抑制剂，具有持续的CNS活性和良好的耐受性。Alectinib是一种新型的，高选择性的，有效的ALK抑制剂，在克唑替尼初始ALK重排NSCLC患者中显示出临床活性。我们对alectinib进行了1/2期研究，以确定该药物的推荐2期剂量，并检查其在对克里唑替尼耐药或不耐受的患者中的活性。方法我们招募了接受克唑替尼治疗进展或不耐受的alk重排非小细胞肺癌患者。在研究的剂量递增阶段（第一阶段），我们给药不同剂量的阿勒替尼（300-900毫克，每天两次），以确定第二阶段的推荐剂量。我们使用实体瘤标准（1.1版）中的反应评估标准来研究alectinib在所有基线扫描和至少一次治疗后扫描（CT或MRI）的患者中的活性，并对脑转移患者进行中心放射检查。我们评估了所有接受至少一剂alectinib的患者的安全性。在这里，我们提供了研究的1期部分的数据，其主要目标是建立推荐的2期剂量；第二阶段正在进行中。该试验已在ClinicalTrials.gov注册，编号NCT01588028。结果纳入47例患者。Alectinib耐受性良好，最常见的不良事件是疲劳（14例[30%]，均为1-2级）、肌痛（8例[17%]，均为1-2级）和周围水肿（7例[15%]，1例[2%]，均为3级）。在接受阿勒替尼900 mg每日两次的队列中，记录了两例患者的剂量限制性毒性作用；一个人有三级头痛，另一个有三级中性粒细胞减少症。最常见的3-4级不良事件是γ -谷氨酰转肽酶水平升高（2例[4%]）、中性粒细胞数量减少（2例[4%]）和低磷血症（2例[4%]）。3名患者报告了4个被认为与阿勒替尼无关的4级严重不良事件：急性肾功能衰竭；胸腔积液和心包积液；还有脑转移。在数据截止时（中位随访126天[IQR 84-217]）， 44例患者可进行活动评估。研究者评估了24例（55%）患者的客观反应，其中1例（2%）患者证实完全缓解，14例（32%）患者证实部分缓解，9例（20%）患者未证实部分缓解。病情稳定16例（36%）；其余4例（9%）为进行性疾病。在21例基线时发生中枢神经系统转移的患者中，11例（52%）有客观缓解；6例（29%）完全缓解（3例未经证实），5例（24%）部分缓解（1例未经证实）；8例（38%）患者病情稳定，其余2例（10%）患者病情进展。药代动力学数据表明，多剂量alectinib （300- 600mg，每天两次）后的平均暴露量（AUC(0-10)）是剂量依赖性的。Alectinib耐受性良好，在对克里唑替尼耐药的alk重排NSCLC患者（包括中枢神经系统转移患者）中具有良好的抗肿瘤活性。基于活性、耐受性和药代动力学数据，我们选择alectinib 600 mg，每天2次作为2期的推荐剂量。
Background Patients with non-small-cell lung cancer (NSCLC) and ALK rearrangements generally have a progression-free survival of 8-11 months while on treatment with the ALK inhibitor crizotinib. However, resistance inevitably develops, with the brain a common site of progression. More potent ALK inhibitors with consistently demonstrable CNS activity and good tolerability are needed urgently. Alectinib is a novel, highly selective, and potent ALK inhibitor that has shown clinical activity in patients with crizotinib-naive ALK-rearranged NSCLC. We did a phase 1/2 study of alectinib to establish the recommended phase 2 dose of the drug and examine its activity in patients resistant or intolerant to crizotinib.Methods We enrolled patients with ALK-rearranged NSCLC who progressed on or were intolerant to crizotinib. We administered various oral doses of alectinib (300-900 mg twice a day) during the dose-escalation portion of the study (phase 1), to ascertain the recommended dose for phase 2. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.1) to investigate the activity of alectinib in all patients with a baseline scan and at least one post-treatment scan (CT or MRI), with central radiological review of individuals with brain metastases. We assessed safety in all patients who received at least one dose of alectinib. Here, we present data for the phase 1 portion of the study, the primary objective of which was to establish the recommended phase 2 dose; phase 2 is ongoing. This trial is registered at ClinicalTrials.gov, number NCT01588028.Findings 47 patients were enrolled. Alectinib was well tolerated, with the most common adverse events being fatigue (14 [30%]; all grade 1-2), myalgia (eight [17%]; all grade 1-2), and peripheral oedema (seven [15%] grade 1-2, one [2%] grade 3). Dose-limiting toxic effects were recorded in two patients in the cohort receiving alectinib 900 mg twice a day; one individual had grade 3 headache and the other had grade 3 neutropenia. The most common grade 3-4 adverse events were increased levels of gamma-glutamyl transpeptidase (two [4%]), a reduction in the number of neutrophils (two [4%]), and hypophosphataemia (two [4%]). Three patients reported four grade 4 serious adverse events that were deemed unrelated to alectinib: acute renal failure; pleural effusion and pericardial effusion; and brain metastasis. At data cut-off (median follow-up 126 days [IQR 84-217]), 44 patients could be assessed for activity. Investigator-assessed objective responses were noted in 24 (55%) patients, with a confirmed complete response in one (2%), a confirmed partial response in 14 (32%), and an unconfirmed partial response in nine (20%). 16 (36%) patients had stable disease; the remaining four (9%) had progressive disease. Of 21 patients with CNS metastases at baseline, 11 (52%) had an objective response; six (29%) had a complete response (three unconfirmed) and five (24%) had a partial response (one unconfirmed); eight (38%) patients had stable disease and the remaining two (10%) had progressive disease. Pharmacokinetic data indicated that mean exposure (AUC(0-10)) after multiple doses of alectinib (300-600 mg twice a day) was dose-dependent.Interpretation Alectinib was well tolerated, with promising antitumour activity in patients with ALK-rearranged NSCLC resistant to crizotinib, including those with CNS metastases. On the basis of activity, tolerability, and pharmacokinetic data, we chose alectinib 600 mg twice a day as the recommended dose for phase 2.