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Title: Clinical Management of Adverse Events Associated with Lorlatinib.
Author: Bauer TM, Felip E, Solomon BJ, Thurm H, Peltz G, Chioda MD, Shaw AT.
Journal: Oncologist; 2019 Aug; 24(8):1103-1110. PubMed ID: 30890623.
Abstract:
Lorlatinib is a novel, highly potent, brain-penetrant, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI), which has broad-spectrum potency against most known resistance mutations that can develop during treatment with crizotinib and second-generation ALK TKIs. The safety profile of lorlatinib was established based on 295 patients who had received the recommended dose of lorlatinib 100 mg once daily. Adverse events associated with lorlatinib are primarily mild to moderate in severity, with hypercholesterolemia (82.4%), hypertriglyceridemia (60.7%), edema (51.2%), peripheral neuropathy (43.7%), and central nervous system effects (39.7%) among the most frequently reported. These can be effectively managed with dose modification and/or standard supportive medical therapy, as indicated by a low incidence of permanent discontinuations due to adverse reactions. Most patients (81.0%) received at least one lipid-lowering agent. Prescription of supportive therapy should also consider the potential for drug-drug interactions with lorlatinib via engagement of specific CYP450 enzymes. This article summarizes the clinical experience from lorlatinib phase I investigators and was generated from discussion and review of the clinical study protocol and database to provide an expert consensus opinion on the management of the key adverse reactions reported with lorlatinib, including hyperlipidemia, central nervous system effects, weight increase, edema, peripheral neuropathy, and gastrointestinal effects. Overall, lorlatinib 100 mg once daily has a unique safety profile to be considered when prescribed, based on the recent U.S. Food and Drug Administration approval, for the treatment of patients with ALK-positive metastatic non-small cell lung cancer previously treated with a second-generation ALK TKI. IMPLICATIONS FOR PRACTICE: Despite the advancement of second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs), the emergence of resistance and progression of central nervous system metastases remain clinically significant problems in ALK-positive non-small cell lung cancer. Lorlatinib is a potent, brain-penetrant, third-generation, macrocyclic ALK/ROS1 TKI, with broad-spectrum potency against most known resistance mutations that can develop during treatment with existing first- and second-generation ALK TKIs. This article provides recommendations for the clinical management of key adverse reactions reported with lorlatinib. 摘要劳拉替尼是一种新型、高效、具有脑渗透作用的第三代 ALK/ROS1 酪氨酸激酶抑制剂 (TKI)，对克唑替尼和第二代 ALK TKI 治疗期间可能发生的大多数已知耐药突变具有广谱效力。295 名患者每日服用一次 100 mg 推荐剂量的劳拉替尼，在此基础上确立了劳拉替尼的安全谱。劳拉替尼相关不良事件的严重程度主要为轻度至中度，最常报告的不良事件是高胆固醇血症 (82.4%)、高甘油三酯血症 (60.7%)、水肿 (51.2%)、周围神经病变 (43.7%) 和中枢神经系统影响 (39.7%)。由于因不良事件引起的永久停药的发生率较低，因此可通过调整剂量和/或标准支持性药物疗法来有效管理上述不良事件。大多数患者 (81.0%) 服用至少一种降脂药。支持疗法的处方还应考虑劳拉替尼通过特定 CYP450 酶的参与发生药物相互作用的可能性。本文总结了劳拉替尼 I 期研究者的临床经验，并通过对临床研究方案和数据库的讨论和回顾，就报告的罗拉替尼主要不良事件(包括高脂血症、中枢神经系统影响、体重增加、水肿、周围神经病变和胃肠影响)的管理提供了专家共识意见。总体而言，根据美国食品药品监督管理局最新的批准，我们认为，凭处方每天服用一次 100 mg 的劳拉替尼对治疗 ALK 阳性转移性非小细胞肺癌患者(之前接受过第二代 ALK TKI 治疗)具有出色的安全性。 实践意义:尽管第二代间变性淋巴瘤激酶 (ALK) 酪氨酸激酶抑制剂 (TKI) 取得了发展，但中枢神经系统转移出现耐药性和进展仍是 ALK 阳性非小细胞肺癌面临的重要临床问题。劳拉替尼是一种高效、具有脑渗透作用的第三代大环 ALK/ROS1 TKI，对现有第一代和第二代 ALK TKI 治疗期间可能发生的大多数已知耐药突变具有广谱效力。本文为报告的劳拉替尼主要不良反应的临床管理提供了建议。

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