Brain Penetration of Lorlatinib: Cumulative Incidences of CNS and Non-CNS Progression with Lorlatinib in Patients with Previously Treated ALK-Positive Non-Small-Cell Lung Cancer
Brain Penetration of Lorlatinib: Cumulative Incidences of CNS and Non-CNS Progression with Lorlatinib in Patients with Previously Treated ALK-Positive Non-Small-Cell Lung Cancer
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DOI：
10.1007/s11523-020-00702-4
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发表时间：
2020-02-01
影响因子：
5.4
通讯作者：
Felip, Enriqueta
中科院分区：
文献类型：
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作者：
Bauer, Todd M.;Shaw, Alice T.;Felip, Enriqueta
背景劳拉替尼是一种强效的第三代ALK/ROS 1酪氨酸激酶抑制剂（TKI），旨在穿透血脑屏障。目的我们报告了既往接受过ALK TKI治疗的ALK阳性非小细胞肺癌（NSCLC）患者接受劳拉替尼治疗后中枢神经系统（CNS）和非CNS进展的累积发生率。患者和方法在一项正在进行的II期研究（NCT 01970865）中，198例既往接受过≥ 1次ALK TKI治疗的ALK阳性NSCLC患者根据治疗史入组扩展队列（EXP）。患者接受劳拉替尼100 mg每日一次。通过独立中心审查，分析患者的疾病进展，分类为CNS或非CNS进展。采用竞争风险方法计算累积发生概率。结果59例患者接受克唑替尼作为其唯一的既往ALK TKI（EXP 2 -3A）;基线CNS转移患者（n = 37）12个月时CNS和非CNS进展的累积发生率（CIR）均为22%，在基线无CNS转移的患者中，12个月时非CNS进展的CIR高于CNS进展的CIR [43% vs. 9%（n = 10）]。22）]。在既往接受≥ 1次第二代ALK TKI [EXP 3B-5（n = 139）]的患者中，12个月时非CNS进展的CIR高于基线时有和无CNS转移的患者中的CNS进展的CIR（分别为35% vs. 23%（n = 94）和55% vs. 12%（n = 45））。结论：劳拉替尼在克唑替尼或第二代ALK TKI治疗后疾病进展的、伴有或不伴有基线CNS转移的ALK阳性NSCLC患者中显示出显著的颅内活性。ClinicalTrials.gov标识符NCT 01970865。
Background Lorlatinib is a potent, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) designed to penetrate the blood-brain barrier. Objective We report the cumulative incidence of central nervous system (CNS) and non-CNS progression with lorlatinib in patients with ALK-positive non-small-cell lung cancer (NSCLC) previously treated with ALK TKIs. Patients and methods In an ongoing phase II study (NCT01970865), 198 patients with ALK-positive NSCLC with >= 1 prior ALK TKI were enrolled into expansion cohorts (EXP) based on treatment history. Patients received lorlatinib 100 mg once daily. Patients were analyzed for progressive disease, categorized as CNS or non-CNS progression, by independent central review. Cumulative incidence probabilities were calculated adopting a competing risks approach. Results Fifty-nine patients received crizotinib as their only prior ALK TKI (EXP2-3A); cumulative incidence rates (CIRs) of CNS and non-CNS progression were both 22% at 12 months in patients with baseline CNS metastases (n = 37), and CIR of non-CNS progression at 12 months was higher versus that for CNS progression in patients without baseline CNS metastases [43% vs. 9% (n = 22)]. In patients who received >= 1 prior second-generation ALK TKI [EXP3B-5 (n = 139)], CIR of non-CNS progression at 12 months was higher versus that for CNS progression in patients both with and without baseline CNS metastases (35% vs. 23% (n = 94) and 55% vs. 12% (n = 45), respectively). Conclusions Lorlatinib showed substantial intracranial activity in patients with pretreated ALK-positive NSCLC, with or without baseline CNS metastases, whose disease progressed on crizotinib or second-generation ALK TKIs. ClinicalTrials.gov identifier NCT01970865.