Introduction

. Lorlatinib is a potent, brain penetrant, next generation ALK/ROS1 TKI, with high response rates and durable responses, including the brain. However, a significant drawback is the manifestation of neurocognitive adverse events (NCAEs). Despite being generally low-grade in severity, these NCAEs can be physically and mentally disabling. Extensive neurocognitive testing in this group of patients is lacking; therefore we conducted this study.

Patients and methods

This observational prospective study was conducted across 3 Dutch university hospitals. Patients with metastatic NSCLC with an ALK- or ROS1-rearrangement, and having an indication to start lorlatinib in daily clinical practice were eligible. The primary endpoints were to identify changes in neurocognitive functioning, measured through neurocognitive assessment at intervals of two weeks and two months after starting of lorlatinib, in comparison to baseline. As secondary endpoint, the correlation between neurocognitive impairment and self-reported neurocognitive dysfunction was examined.

Results

Between June 2019 and October 2022, 22 patients were included. Among the various neurocognitive tests administered, only the Hopkins Verbal Learning Test-Revised part b and c demonstrated a significant and clinically relevant decrease in scoring two weeks post-initiation of lorlatinib (p=0.036 and p=0.003, respectively). However, these returned to baseline at the two-month evaluation. The questionnaires did not result in significantly different outcomes over time.

Conclusion

lorlatinib treatment did not result in a sustained and significant decline within any of the specified neurocognitive domains.

Micro abstract

Lorlatinib represents a potent, and brain penetrant, next generation ALK/ROS1 TKI. Despite significant efficacy, a notable drawback is the emergence of neurocognitive adverse events (NCAEs). Our multicenter study involving comprehensive neurocognitive assessments failed to reveal a sustained deterioration within any of the assessed neurocognitive domains.

中文翻译：

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深度分析劳拉替尼相关非小细胞肺癌患者神经认知不良事件

 介绍

。 Lorlatinib 是一种强效、脑渗透性的下一代 ALK/ROS1 TKI，具有高反应率和持久反应，包括大脑。然而，一个显着的缺点是神经认知不良事件（NCAE）的表现。尽管这些 NCAE 的严重程度通常较低，但可能会造成身体和精神上的残疾。对这组患者缺乏广泛的神经认知测试；因此我们进行了这项研究。

 患者和方法

这项观察性前瞻性研究是在荷兰 3 所大学医院进行的。具有 ALK 或 ROS1 重排的转移性 NSCLC 患者，并且有在日常临床实践中开始使用劳拉替尼的指征，符合资格。主要终点是确定神经认知功能的变化，通过洛拉替尼开始后每隔两周和两个月进行神经认知评估来测量，与基线相比。作为次要终点，检查了神经认知障碍和自我报告的神经认知障碍之间的相关性。

 结果

2019年6月至2022年10月期间，纳入了22名患者。在进行的各种神经认知测试中，只有霍普金斯言语学习测试修订版 b 和 c 部分显示，在开始使用 lorlatinib 两周后，评分出现显着且具有临床意义的下降（分别为 p=0.036 和 p=0.003）。然而，这些在两个月的评估中回到了基线。随着时间的推移，调查问卷并没有产生显着不同的结果。

 结论

劳拉替尼治疗并未导致任何特定神经认知领域持续显着下降。

 微摘要

Lorlatinib 代表了一种有效的、具有脑渗透性的下一代 ALK/ROS1 TKI。尽管疗效显着，但一个显着的缺点是神经认知不良事件（NCAE）的出现。我们涉及全面神经认知评估的多中心研究未能揭示任何评估的神经认知领域的持续恶化。