Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial
Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial
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DOI：
10.1200/jco.2016.71.5904
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发表时间：
2017-08-01
影响因子：
45.3
通讯作者：
Camidge, D. Ross
中科院分区：
文献类型：
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作者：
Kim, Dong-Wan;Tiseo, Marcello;Camidge, D. Ross
大多数接受克唑替尼治疗的间变性淋巴瘤激酶基因（ALK）重排的非小细胞肺癌（ALK阳性NSCLC）患者最终会出现疾病进展。我们评估了两种方案的brigatinib，研究下一代ALK抑制剂，在克唑替尼难治性ALK阳性NSCLC.Patients and MethodsPatients分层的脑转移和最佳反应克唑替尼。他们被随机（1：1）分配至口服brigatinib 90 mg每日一次（A组）或180 mg每日一次，90 mg导入期7天（180 mg每日一次[导入期]; B组）。研究者评估确认的客观反应率（ORR）是主要的终点。ResultsOf 222例患者（A组：n = 112，109治疗;臂B：n = 110，110治疗），154（69%）有基线脑转移和164 222（74%）已接受过化疗。中位随访期为8.0个月，A组和B组中经评估确认的ORR分别为45%（97.5% CI，34%-56%）和54%（97.5% CI，43%-65%）。A组和B组研究者评估的中位无进展生存期分别为9.2个月（95% CI，7.4 - 15.6）和12.9个月（95% CI，11.1-未达到）。在A组和B组中，独立审查委员会评估的基线时具有可测量脑转移的患者的颅内ORR分别为42%（11/26例患者）和67%（12/18例患者）。常见的治疗后出现的不良事件为恶心（A/B组，33%/ 40%）、腹泻（A/B组，19%/38%）、头痛（A/B组，28%/27%）和咳嗽（A/B组，18%/ 34%），主要为1 - 2级。219例接受治疗的患者中有14例（所有级别，6%; ≥ 3级，3%）发生了早发性（中位发生时间：第2天）肺部不良事件子集; B组中剂量递增至180 mg后未发生此类事件。14例患者中有7例成功地重新接受了brigatinib治疗。结论Brigatinib产生了显著的全身和颅内反应以及稳健的无进展生存期; 180 mg（导入）显示出持续优于90 mg的疗效，安全性可接受。(C)2017年美国临床肿瘤学会
PurposeMost crizotinib-treated patients with anaplastic lymphoma kinase gene (ALK)-rearranged non-smallcell lung cancer (ALK-positive NSCLC) eventually experience disease progression. We evaluated two regimens of brigatinib, an investigational next-generation ALK inhibitor, in crizotinib-refractory ALK-positive NSCLC.Patients and MethodsPatients were stratified by brain metastases and best response to crizotinib. They were randomly assigned (1: 1) to oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (180 mg once daily [with lead-in]; arm B). Investigator-assessed confirmed objective response rate (ORR) was the primary end point.ResultsOf 222 patients enrolled (arm A: n = 112, 109 treated; arm B: n = 110, 110 treated), 154 (69%) had baseline brain metastases and 164 of 222 (74%) had received prior chemotherapy. With 8.0-month median follow-up, investigator-assessed confirmed ORR was 45% (97.5% CI, 34% to 56%) in arm A and 54% (97.5% CI, 43% to 65%) in arm B. Investigator-assessed median progression-free survival was 9.2 months (95% CI, 7.4 to 15.6) and 12.9 months (95% CI, 11.1 to not reached) in arms A and B, respectively. Independent review committee-assessed intracranial ORR in patients with measurable brain metastases at baseline was 42% (11 of 26 patients) in arm A and 67% (12 of 18 patients) in arm B. Common treatment-emergent adverse events were nausea (arm A/B, 33%/ 40%), diarrhea (arm A/B, 19%/38%), headache (arm A/B, 28%/27%), and cough (arm A/B, 18%/ 34%), and were mainly grades 1 to 2. A subset of pulmonary adverse events with early onset (median onset: day 2) occurred in 14 of 219 treated patients (all grades, 6%; grade >= 3, 3%); none occurred after escalation to 180 mg in arm B. Seven of 14 patients were successfully retreated with brigatinib.Conclusion Brigatinib yielded substantial whole-body and intracranial responses as well as robust progressionfree survival; 180 mg (with lead-in) showed consistently better efficacy than 90 mg, with acceptable safety. (C) 2017 by American Society of Clinical Oncology