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Abstract：
WHAT IS KNOWN AND OBJECTIVE?: Leptomeningeal metastasis (LM) is a serious complication of advanced non-small cell lung cancer (NSCLC) that is diagnosed in approximately 3%-5% of patients. LM occurs more frequently in patients with NSCLC harbouring epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements and is usually accompanied by a poor prognosis, with a median overall survival (OS) of several months if patients receive conventional treatments. However, tyrosine kinase inhibitor (TKI) therapy after LM diagnosis is an independent predictive factor for extended survival. Here, we aim to summarize the latest advances in targeted therapy for LM and provide patients with better treatment options. METHODS: By reviewing the recent progress of targeted therapy in NSCLC with LM, especially the efficacy of newer generation TKIs, we aim to provide clinicians with a reference to further optimize patient treatment plans. RESULTS AND DISCUSSION: Osimertinib was confirmed to have a several-fold higher CNS permeability than other EGFR-TKIs and was recommended as the preferred choice for patients with EGFR-positive LM whether or not they harboured the T790M mutation. Second-generation ALK-TKIs have a higher rate of intracranial response and can be positioned as front-line drugs in NSCLC with LM. However, the sequence in which ALK-TKIs are administered for effective disease control requires further evaluation. In addition, targeted therapy revealed a potential choice in patients with LM and rare mutations, such as ROS1 and BRAF. WHAT IS NEW AND CONCLUSIONS?: The development of therapeutic agents with greater CNS penetration is vital for the management of CNS metastasis from NSCLC, particularly in the EGFR-mutant and ALK-rearranged subtypes. Systemic therapy with newer generation TKIs is preferred as the initial intervention. This is because newer generation TKIs are designed to penetrate the blood-brain barrier and possess significantly higher intracranial activities. However, their further effectiveness is limited by inadequate blood-brain barrier penetration and acquired drug resistance. Further studies are needed to further understand the mechanisms underlying resistance to treatment.
摘要：
什么是已知和目标？：脑膜转移（LM）是晚期非小细胞肺癌（NSCLC）的严重并发症，约3％-5％的患者被诊断出。LM在包含表皮生长因子受体（EGFR）突变或间变性淋巴瘤激酶（ALK）重排的NSCLC患者中更常见，通常伴有不良预后。如果患者接受常规治疗，则中位总生存期（OS）为几个月。然而,LM诊断后的酪氨酸激酶抑制剂（TKI）治疗是延长生存期的独立预测因素。这里,我们旨在总结LM靶向治疗的最新进展,为患者提供更好的治疗方案.方法:通过回顾肺癌靶向治疗的最新进展,特别是新一代TKIs的功效，我们旨在为临床医生提供进一步优化患者治疗计划的参考。结果与讨论：奥希替尼被证实具有比其他EGFR-TKIs高几倍的CNS通透性，并被推荐为EGFR阳性LM患者的首选，无论他们是否携带T790M突变。第二代ALK-TKIs具有较高的颅内反应率，可作为NSCLC伴LM的一线药物。然而,为了有效控制疾病,ALK-TKIs的给药顺序需要进一步评估.此外,靶向治疗揭示了LM和罕见突变患者的潜在选择，如ROS1和BRAF。什么是新的和结论？：开发具有更大中枢神经系统渗透的治疗剂对于NSCLC中枢神经系统转移的管理至关重要，特别是在EGFR突变和ALK重排亚型中。使用新一代TKIs的系统治疗是首选的初始干预措施。这是因为新一代TKIs被设计为穿透血脑屏障并具有明显更高的颅内活动。然而,它们的进一步有效性受到血脑屏障渗透不足和获得性耐药性的限制。需要进一步研究以进一步了解对治疗耐药的潜在机制。
