IMPORTANCE Ensartinib, an oral tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system efficacy for patients with ALK-positive non-small cell lung cancer (NSCLC). OBJECTIVE To compare ensartinib with crizotinib among patients with advanced ALK-positive NSCLC who had not received prior treatment with an ALK inhibitor. DESIGN, SETTING, AND PARTICIPANTS This open-label, multicenter, randomized, phase 3 trial conducted in 120 centers in 21 countries enrolled 290 patients between July 25, 2016, and November 12, 2018. Eligible patients were 18 years of age or older and had advanced, recurrent, or metastatic ALK-positive NSCLC. INTERVENTIONS Patients were randomized (1:1) to ensartinib, 225 mg once daily, or crizotinib, 250 mg twice daily. MAIN OUTCOMES AND MEASURES The primary end point was blinded independent review committee-assessed progression-free survival (PFS). Secondary end points included systemic and intracranial response, time to central nervous system progression, and overall survival. Efficacy was evaluated in the intent-to-treat (ITT) population as well as a prespecified modified ITT (mITT) population consisting of patients with central laboratory-confirmed ALK-positive NSCLC. RESULTS A total of 290 patients (149 men [51.4%]; median age, 54 years [range, 25-90 years]) were randomized. In the ITT population, the median PFS was significantly longer with ensartinib than with crizotinib (25.8 [range, 0.03-44.0 months] vs 12.7 months [range, 0.03-38.6 months]; hazard ratio, 0.51 [95% CI, 0.35-0.72]; log-rank P < .001), with a median follow-up of 23.8 months (range, 0-44 months) for the ensartinib group and 20.2 months (range, 0-38 months) for the crizotinib group. In the mITT population, the median PFS in the ensartinib group was not reached, and the median PFS in the crizotinib group was 12.7 months (95% CI, 8.9-16.6 months; hazard ratio, 0.45; 95% CI, 0.30-0.66; log-rank P < .001). The intracranial response rate confirmed by a blinded independent review committee was 63.6% (7 of 11) with ensartinib vs 21.1% (4 of 19) with crizotinib for patients with target brain metastases at baseline. Progression-free survival for patients without brain metastases was not reached with ensartinib vs 16.6 months with crizotinib as a result of a lower central nervous system progression rate (at 12 months: 4.2% with ensartinib vs 23.9% with crizotinib; cause-specific hazard ratio, 0.32; 95% CI, 0.16-0.63; P = .001). Frequencies of treatment-related serious adverse events (ensartinib: 11 [7.7%] vs crizotinib: 9 [6.1%]), dose reductions (ensartinib: 34 of 143 [23.8%] vs crizotinib: 29 of 146 [19.9%]), or drug discontinuations (ensartinib: 13 of 143 [9.1%] vs crizotinib: 10 of 146 [6.8%]) were similar, without any new safety signals. CONCLUSIONS AND RELEVANCE In this randomized clinical trial, ensartinib showed superior efficacy to crizotinib in both systemic and intracranial disease. Ensartinib represents a new first-line option for patients with ALK-positive NSCLC. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02767804.

中文翻译：

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Ensartinib vs Crizotinib 治疗间变性淋巴瘤激酶阳性非小细胞肺癌患者：一项随机临床试验。

重要性 Ensartinib 是一种间变性淋巴瘤激酶 (ALK) 的口服酪氨酸激酶抑制剂，已显示对 ALK 阳性非小细胞肺癌 (NSCLC) 患者的全身和中枢神经系统疗效。目的比较恩沙替尼与克唑替尼在既往未接受过 ALK 抑制剂治疗的晚期 ALK 阳性 NSCLC 患者中的疗效。设计、设置和参与者 这项开放标签、多中心、随机、3 期试验在 21 个国家的 120 个中心进行，于 2016 年 7 月 25 日至 2018 年 11 月 12 日期间招募了 290 名患者。符合条件的患者年龄在 18 岁或以上，并且患有晚期、复发性或转移性 ALK 阳性 NSCLC。干预 患者被随机分配 (1:1) 接受恩沙替尼 225 mg 每天一次或克唑替尼 250 mg 每天两次。主要结果和测量 主要终点是盲法独立审查委员会评估的无进展生存期（PFS）。次要终点包括全身和颅内反应、中枢神经系统进展时间和总生存期。在意向治疗 (ITT) 人群以及由中心实验室确诊的 ALK 阳性 NSCLC 患者组成的预先指定的改良 ITT (mITT) 人群中评估疗效。结果 共有 290 名患者（149 名男性 [51.4%]；中位年龄，54 岁 [范围，25-90 岁]）被随机分组​​。在 ITT 人群中，恩沙替尼的中位 PFS 显着长于克唑替尼（25.8 [范围，0.03-44.0 个月] vs 12.7 个月 [范围，0.03-38.6 个月]；风险比，0.51 [95% CI，0.35-0.72 ]；对数秩 P < .001），中位随访时间为 23.8 个月（范围，恩沙替尼组为 0-44 个月），克唑替尼组为 20.2 个月（范围，0-38 个月）。在mITT人群中，恩沙替尼组的中位PFS未达到，克唑替尼组的中位PFS为12.7个月（95% CI，8.9-16.6个月；风险比，0.45；95% CI，0.30-0.66；对数秩 P < .001）。一个盲法独立审查委员会证实，对于基线时有靶脑转移的患者，恩沙替尼组的颅内缓解率为 63.6%（11 人中的 7 人），而克唑替尼组为 21.1%（19 人中的 4 人）。由于中枢神经系统进展率较低（12个月时：恩沙替尼组为4.2%，克唑替尼组为23.9%；原因特异性风险比） ，0.32；95% CI，0.16-0.63；P = .001）。治疗相关严重不良事件的频率（恩沙替尼：11 [7.7%] vs 克唑替尼：9 [6.1%]），剂量减少（恩沙替尼：143 例中的 34 例 [23.8%] vs 克唑替尼：146 例中的 29 例 [19.9%]），或药物停药（恩沙替尼：143 例中的 13 例 [9.1%] 与克唑替尼：146 例中的 10 例 [6.8%]）相似，没有任何新的安全信号。结论和相关性 在这项随机临床试验中，恩沙替尼在全身性疾病和颅内疾病中均显示出优于克唑替尼的疗效。Ensartinib 代表了 ALK 阳性 NSCLC 患者的新一线选择。试验注册 ClinicalTrials.gov 标识符：NCT02767804。1%] 与克唑替尼：146 个中的 10 个 [6.8%]) 相似，没有任何新的安全信号。结论和相关性 在这项随机临床试验中，恩沙替尼在全身性疾病和颅内疾病中均显示出优于克唑替尼的疗效。Ensartinib 代表了 ALK 阳性 NSCLC 患者的新一线选择。试验注册 ClinicalTrials.gov 标识符：NCT02767804。1%] 与克唑替尼：146 个中的 10 个 [6.8%]) 相似，没有任何新的安全信号。结论和相关性 在这项随机临床试验中，恩沙替尼在全身性疾病和颅内疾病中均显示出优于克唑替尼的疗效。Ensartinib 代表了 ALK 阳性 NSCLC 患者的新一线选择。试验注册 ClinicalTrials.gov 标识符：NCT02767804。