Several anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors have been developed for the treatment of EML4-ALK-rearranged non-small-cell lung cancer, with the newer generation agents brigatinib, alectinib and lorlatinib showing pronounced central nervous system activities. Intracranial efficacy is an important feature for these agents, as metastatic lesions frequently occur in the central nervous system in the ALK-positive setting. Here, we report on an updated case of a patient who received her diagnosis in 2005 and has had disease progression with new lesions on six occasions over the last 8 years. During the first two progressions, only local recurrence was observed. After that, the lungs stayed clear and the patient progressed exclusively in the brain and spinal cord. Initial treatments consisted of chemotherapy and radiotherapy. In 2012, ALK-directed targeted therapy became available, and crizotinib was administered. The treatment was switched to brigatinib 3 years later because of spinal cord lesions. Brigatinib induced partial remission and was followed by lorlatinib and, later on, alectinib, when new metastases arose in the spinal cord and brain. Each of these drugs promoted complete remission of the recent lesions. In November 2018, imaging showed multiple cerebral metastases. As radiotherapy was not an option because of previous irradiation, and as chemotherapy cannot be expected to be active in the brain, the patient underwent brigatinib rechallenge, which led to partial remission. All of the central nervous system relapses were symptomatic, with symptoms resolved rapidly during treatment. This case of a patient with EML4-ALK-rearranged non-small-cell lung cancer shows that sequential treatment with next-generation ALK tyrosine kinase inhibitors, including rechallenge, can induce profound remission even in heavily pretreated patients, especially if the central nervous system is the site of progression.