Lorlatinib在非小细胞肺癌筛选或ROS1重排:一个国际多中心、非盲、单臂第一次作用于人体的第一阶段试验。

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肖,Felip E,鲍尔TM,贝斯B(纳瓦罗,Postel-Vinay年代,Gainor摩根富林明,约翰逊M,迪特里希J,詹姆斯•LP克兰西JS,陈J,马提尼摩根富林明,Abbattista,所罗门BJ

Lorlatinib在非小细胞肺癌筛选或ROS1重排:一个国际多中心、非盲、单臂第一次作用于人体的第一阶段试验。

柳叶刀杂志。2017;12月18日(12):1590 - 1599。doi: 10.1016 / s1470 - 2045 (17) 30680 - 0。Epub 2017年10月23日。

PubMed ID
29074098 (在PubMed
]
文摘

背景:大多数患者间变性淋巴瘤激酶(碱性)重新安排或ROS原癌基因1 (ROS1)重新安排非小细胞肺癌(NSCLC)酪氨酸激酶抑制剂(TKI)治疗很敏感,但阻力总是发展,通常在中枢神经系统内。本研究旨在分析安全、功效、lorlatinib和药代动力学性质,一部小说,高度的选择性,和brain-penetrant alaska airlines ROS1 TKI临床活动对大多数已知电阻突变,在高级ALK-positive或ROS1-positive NSCLC患者。方法:在这个国际多中心、非盲、随访时间,第一次作用于人体的剂量递增第一阶段学习,符合条件的患者晚期ALK-positive或ROS1-positive NSCLC,年龄超过18岁,与东部合作肿瘤组0或1的性能状态,和足够的终末器官功能。Lorlatinib是口服药物病人从10毫克剂量200毫克每日一次或35毫克100毫克每日两次,用最少的三个病人接受剂量。对于一些患者,肿瘤活检是lorlatinib治疗前确定筛选抗性突变。安全评估病人至少一剂lorlatinib;疗效评估的意向处理人口(病人至少一剂研究治疗和碱性或ROS1重排)。主要终点是dose-limiting毒性在周期1根据调查评估;次级终点包括安全、药物动力学和总体响应。这项研究正在进行,在ClinicalTrials.gov注册,NCT01970865数量。 FINDINGS: Between Jan 22, 2014, and July 10, 2015, 54 patients received at least one dose of lorlatinib, including 41 (77%) with ALK-positive and 12 (23%) with ROS1-positive NSCLC; one patient had unconfirmed ALK and ROS1 status. 28 (52%) patients had received two or more TKIs, and 39 (72%) patients had CNS metastases. The most common treatment-related adverse events among the 54 patients were hypercholesterolaemia (39 [72%] of 54 patients), hypertriglyceridaemia (21 [39%] of 54 patients), peripheral neuropathy (21 [39%] of 54 patients), and peripheral oedema (21 [39%] of 54 patients). One dose-limiting toxicity occurred at 200 mg (the patient did not take at least 16 of 21 prescribed total daily doses in cycle 1 because of toxicities attributable to study drug, which were grade 2 neurocognitive adverse events comprising slowed speech and mentation and word-finding difficulty). No maximum tolerated dose was identified. The recommended phase 2 dose was selected as 100 mg once daily. For ALK-positive patients, the proportion of patients who achieved an objective response was 19 (46%) of 41 patients (95% CI 31-63); for those who had received two or more TKIs, the proportion of patients with an objective response was 11 (42%) of 26 patients (23-63). In ROS1-positive patients, including seven crizotinib-pretreated patients, an objective response was achieved by six (50%) of 12 patients (95% CI 21-79). INTERPRETATION: In this phase 1, dose-escalation study, lorlatinib showed both systemic and intracranial activity in patients with advanced ALK-positive or ROS1-positive NSCLC, most of whom had CNS metastases and had previously had two or more TKI treatments fail. Therefore, lorlatinib might be an effective therapeutic strategy for patients with ALK-positive NSCLC who have become resistant to currently available TKIs, including second-generation ALK TKIs, and is being investigated in a phase 3 randomised controlled trial comparing lorlatinib to crizotinib (ClinicalTrials.gov, NCT03052608). FUNDING: Pfizer.

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