非小细胞肺癌（NSCLC）患者的生存率得到了改善，这在很大程度上归功于免疫检查点抑制剂和新型靶向治疗对全身性疾病的改善控制，同时也突显了中枢神经系统（CNS）转移作为一种毁灭性但常见并发症所带来的挑战，在疾病过程中高达50%的患者会出现这种病变。早期酪氨酸激酶抑制剂（TKIs）常常在带有致癌基因驱动的NSCLC患者中提供强有力的全身性疾病控制，尽管这些药物通常由于无法穿越血脑屏障而无法在中枢神经系统中积累到治疗相关浓度。然而，在过去的几年里，出现了几种具有改善CNS渗透性的新型或后期发展的TKIs，这标志着范式的转变。此类药物在脑转移研究中表现出很高的活性，这已通过临床前和临床研究的数据得到证实。在本综述中，我们描述了针对NSCLC患者中不同致癌驱动基因的TKIs在颅内活性的当前临床前和临床证据，重点关注具有改善CNS渗透的新型药物、蛛网膜病和脑脊液治疗选择的需求。我们还讨论了未来临床研究的评估标准和监管考虑的演变。© 2023. Springer Nature Limited.

The improved survival outcomes of patients with non-small-cell lung cancer (NSCLC), largely owing to the improved control of systemic disease provided by immune-checkpoint inhibitors and novel targeted therapies, have highlighted the challenges posed by central nervous system (CNS) metastases as a devastating yet common complication, with up to 50% of patients developing such lesions during the course of the disease. Early-generation tyrosine-kinase inhibitors (TKIs) often provide robust systemic disease control in patients with oncogene-driven NSCLCs, although these agents are usually unable to accumulate to therapeutically relevant concentrations in the CNS owing to an inability to cross the blood-brain barrier. However, the past few years have seen a paradigm shift with the emergence of several novel or later-generation TKIs with improved CNS penetrance. Such agents have promising levels of activity against brain metastases, as demonstrated by data from preclinical and clinical studies. In this Review, we describe current preclinical and clinical evidence of the intracranial activity of TKIs targeting various oncogenic drivers in patients with NSCLC, with a focus on newer agents with enhanced CNS penetration, leptomeningeal disease and the need for intrathecal treatment options. We also discuss evolving assessment criteria and regulatory considerations for future clinical investigations.© 2023. Springer Nature Limited.