El Darsa Haidar, Abdel-Rahman Omar, Sangha Randeep
Department of Oncology, University of Alberta, Cross Cancer Institute , Edmonton, Canada.
Expert Opin Pharmacother. 2020 Sep;21(13):1547-1554. doi: 10.1080/14656566.2020.1774552. Epub 2020 Jun 8.
Approximately 3-7% of advanced non-small cell lung cancers (NSCLC) are driven by an anaplastic lymphoma kinase () rearrangement. Crizotinib, ceritinib, alectinib, and brigatinib are active inhibitors (ALKi) used to treat this oncogene-driven subset of NSCLC. Resistance occurs with time to ALKi and new therapeutics are being developed. Lorlatinib is an efficacious third-generation ALKi with an ability to overcome resistance mutations that develop with first- or second-generation ALKi.
Herein, the authors review the mechanism of action, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of lorlatinib and provide their future perspectives on this drug.
Lorlatinib is a potent and inhibitor that also has activity against many acquired resistance mutations. Clinical trials show the robust systemic and intracranial anti-tumor activity of lorlatinib in rearranged advanced NSCLC. Adverse events of lorlatinib are unique and manageable. These include hypocholesteremia, hypertriglyceridemia, edema, cognitive effects, weight gain, and diarrhea. Loratinib will play an increasing role in the management of -rearranged NSCLC with the optimal sequencing of ALKi undergoing further research.
约3%-7%的晚期非小细胞肺癌（NSCLC）由间变性淋巴瘤激酶（ALK）重排驱动。克唑替尼、色瑞替尼、阿来替尼和布加替尼是用于治疗这种由致癌基因驱动的NSCLC亚组的活性ALK抑制剂（ALKi）。随着时间的推移，会出现对ALKi的耐药性，并且正在开发新的治疗方法。洛拉替尼是一种有效的第三代ALKi，能够克服第一代或第二代ALKi产生的耐药突变。
在此，作者回顾了洛拉替尼的作用机制、药代动力学、药效学、临床疗效和安全性，并对该药物给出了未来展望。
洛拉替尼是一种强效的ALK和ROS1抑制剂，对许多获得性ALK耐药突变也有活性。临床试验表明，洛拉替尼在ALK重排的晚期NSCLC中具有强大的全身和颅内抗肿瘤活性。洛拉替尼的不良事件独特但可管理。这些不良事件包括低胆固醇血症、高甘油三酯血症、水肿、认知影响、体重增加和腹泻。随着对ALKi最佳给药顺序的进一步研究，洛拉替尼在ALK重排NSCLC的治疗中将发挥越来越重要作用。
