Updated Efficacy and Safety Data and Impact of the EML4-ALK Fusion Variant on the Efficacy of Alectinib in Untreated ALK-Positive Advanced Non-Small Cell Lung Cancer in the Global Phase III ALEX Study
Updated Efficacy and Safety Data and Impact of the EML4-ALK Fusion Variant on the Efficacy of Alectinib in Untreated ALK-Positive Advanced Non-Small Cell Lung Cancer in the Global Phase III ALEX Study
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DOI：
10.1016/j.jtho.2019.03.007
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发表时间：
2019-07-01
影响因子：
20.4
通讯作者：
Shaw, Alice T.
中科院分区：
文献类型：
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作者：
Camidge, D. Ross;Dziadziuszko, Rafal;Shaw, Alice T.
在先前的数据截止日期（2017年2月9日），ALEX试验显示，在未经治疗的间变淋巴瘤激酶（ALK）阳性的晚期NSCLC中，alectinib优于克唑替尼的研究者评估的无进展生存期（PFS）（风险比= 0.47,95%置信区间：0.34-0.65,p < 0.001）。阿勒替尼组的中位PFS未达到，而克唑替尼组的中位PFS为11.1个月。回顾性分析表明棘皮微管相关蛋白样4基因- alk变异（EML4-ALK）可能影响alk抑制剂的治疗效果。在额外的10个月随访（截止2017年12月1日）后，我们提出了最新的分析，包括EML4-ALK变体的探索性亚组分析。方法：患者随机接受每日两次的阿勒替尼（600mg）或克唑替尼（250mg），直到疾病进展、毒性、死亡或停药。PFS由研究者决定。基线血浆和组织生物标志物样本分析采用混合捕获，下一代测序，以确定EML4-ALK变异。结果：基线特征平衡。研究者评估的PFS延长了阿勒替尼（分层风险比= 0.43,95%可信区间：0.32-0.58）。阿勒替尼组的中位PFS时间为34.8个月，克唑替尼组为10.9个月。在129例患者血浆样本和124例组织样本中检测到EML4-ALK融合；变异1、2和3/ab不影响PFS、客观反应率或反应持续时间。研究者评估的血浆和组织中EML4-ALK变异1、2和3a/b中，阿勒替尼的PFS比克唑替尼长。尽管治疗时间更长（阿勒替尼为27.0个月，克唑替尼为10.8个月），但阿勒替尼的安全性优于克唑替尼。结论：在未治疗的alk阳性NSCLC中，无论EML4-ALK变异如何，Alectinib继续表现出优于克唑替尼的研究者评估的PFS。(C) 2019年国际肺癌研究协会。Elsevier Inc.出版。
Introduction: At the prior data cutoff (February 9, 2017) the ALEX trial showed superior investigator-assessed progression-free survival (PFS) for alectinib versus crizotinib in untreated, anaplastic lymphoma kinase (ALK)-positive, advanced NSCLC (hazard ratio = 0.47, 95% confidence interval: 0.34-0.65, p < 0.001). The median PFS in the alectinib arm was not reached versus 11.1 months with crizotinib. Retrospective analyses suggest that the echinoderm microtubule-associated proteinlike 4 gene-ALK variant (EML4-ALK) may influence ALK-inhibitor treatment benefit. We present updated analyses, including exploratory subgroup analysis by EML4-ALK variant, after an additional 10 months' followup (cutoff December 1, 2017).Methods: Patients were randomized to receive twice-daily alectinib, 600 mg, or crizotinib, 250 mg, until disease progression, toxicity, death, or withdrawal. PFS was determined by the investigators. Baseline plasma and tissue biomarker samples were analyzed by using hybrid-capture, next-generation sequencing to determine EML4-ALK variant.Results: Baseline characteristics were balanced. Investigator-assessed PFS was prolonged with alectinib (stratified hazard ratio = 0.43, 95% confidence interval: 0.32-0.58). The median PFS times were 34.8 months with alectinib and 10.9 months with crizotinib. EML4-ALK fusions were detectable in 129 patient plasma samples and 124 tissue samples; variants 1, 2, and 3/ab did not affect PFS, objective response rate, or duration of response. Investigator-assessed PFS was longer for alectinib than for crizotinib across EML4-ALK variants 1, 2, and 3a/b in plasma and tissue. Despite longer treatment duration (27.0 months in the case of alectinib versus 10.8 months in the case of crizotinib), the safety of alectinib compared favorably with that of crizotinib.Conclusion: Alectinib continues to demonstrate superior investigator-assessed PFS versus crizotinib in untreated ALK-positive NSCLC, irrespective of EML4-ALK variant. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc.