Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial.
Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial.
复制标题
ALECTINIB在ALK阳性，抗克唑替尼，非小细胞肺癌：单组，多中心，第二阶段试验中。
DOI：
10.1016/s1470-2045(15)00488-x
复制
发表时间：
2016-02
期刊：
影响因子：
--
通讯作者：
study investigators
中科院分区：
文献类型：
--
作者：
Shaw AT;Gandhi L;Gadgeel S;Riely GJ;Cetnar J;West H;Camidge DR;Socinski MA;Chiappori A;Mekhail T;Chao BH;Borghaei H;Gold KA;Zeaiter A;Bordogna W;Balas B;Puig O;Henschel V;Ou SI;study investigators
阿莱替尼是一种高选择性、中枢神经系统(CNS)活性的间变性淋巴瘤激酶(ALK)抑制剂，在治疗初治和耐药的非小细胞肺癌(NSCLC)方面显示出良好的临床活性。这项第二阶段的研究评估了阿莱替尼在ALK阳性的NSCLC患者中的安全性和有效性，这些患者之前服用了Crizotinib。这项正在进行的北美研究(NCT01871805)纳入了IIIB/IV ALK阳性非小细胞肺癌患者，这些患者在服用Crizotinib后病情恶化。患者每天两次口服阿来替尼600 mg，直到病情进展、死亡或停药。主要终点是使用RECIST v1.1的独立审查委员会(IRC)的总体应答率(ORR)。次要终点包括无进展生存期(PFS)、反应持续时间(DOR)、颅内ORR和DOR、安全性和患者报告的结果。意向治疗人群用于疗效和安全性分析，可评估反应人群用于反应终点。共有87名患者被纳入意向治疗人群。所有患者都曾接受过克里佐替尼治疗，患者(74%)也曾接受过化疗。52名患者(60%)有基线中枢神经系统转移，其中18名(35%)以前没有接受过脑放射治疗。在初步分析时(中位随访4.8个月)，IRC的ORR为48%(95%可信区间为36~60)。不良反应主要是1级或2级，最常见的是便秘、疲劳、肌痛和周围水肿。最常见的≥3级AEs是实验室指标的改变，包括血肌酸磷酸激酶升高(8%，n=7)、丙氨酸氨基转移酶升高(6%n=5)和天冬氨酸转氨酶升高(5%n=4)。阿莱替尼显示了临床疗效，在服用克里佐替尼的ALK阳性非小细胞肺癌患者中耐受性良好。阿莱替尼在中枢神经系统中是活跃的，大多数对克里佐替尼耐药的中枢神经系统疾病患者的持久反应证明了这一点。因此，阿莱替尼可能是一种合适的治疗方案，用于ALK阳性的疾病患者，这些患者的病情发展到了克里佐替尼。
Alectinib, a highly selective, central nervous system (CNS)-active anaplastic lymphoma kinase (ALK) inhibitor, demonstrated promising clinical activity in crizotinib-naïve and crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC). This phase 2 study evaluated the safety and efficacy of alectinib in ALK-positive NSCLC patients who progressed on previous crizotinib. This ongoing North American study (NCT01871805) enrolled patients with stage IIIB/IV ALK-positive NSCLC, who had progressed following crizotinib. Patients were treated with oral alectinib 600 mg twice daily until progression, death or withdrawal. Primary endpoint was overall response rate (ORR) by independent review committee (IRC) using RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DOR), intracranial ORR and DOR, safety, and patient-reported outcomes. The intent-to-treat population was used for efficacy and safety analyses, with the response evaluable population used for response endpoints. A total of 87 patients were enrolled in the intent-to-treat population. All patients had received prior crizotinib therapy, and 64 patients (74%) had also received prior chemotherapy. Fifty-two patients (60%) had baseline CNS metastases, of whom 18 (35%) had received no prior brain radiation therapy. At the time of primary analysis (median follow-up 4.8 months), ORR by IRC was 48% (95% CI 36–60). Adverse events were predominantly grade 1 or 2, most commonly constipation, fatigue, myalgia and peripheral edema. The most common grade ≥3 AEs were changes in laboratory values, including increased blood creatine phosphokinase (in 8%, n=7), increased alanine aminotransferase (in 6% n=5), and increased aspartate aminotransferase (in 5% n=4). Alectinib demonstrated clinical efficacy and was well tolerated in patients with ALK-positive NSCLC who had progressed on crizotinib. Alectinib was active in the CNS, as demonstrated by durable responses in the majority of crizotinib-resistant patients with CNS disease. Therefore, alectinib could be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib.