Brain Metastases in NSCLC - are TKIs Changing the Treatment Strategy?

Non-small-cell lung cancer (NSCLC) ranks as a leading cause of cancer-related death globally. Brain metastases are a frequent complication of NSCLC, with 25-40% of patients developing brain metastases during the course of the disease, often within the first 2 years after diagnosis of the primary tumor. Improvements in neurological symptoms and performance status have been reported with whole-brain radiation therapy (WBRT) in combination with steroid therapy in NSCLC patients. In addition, a survival benefit has been reported for patients with a single brain metastasis treated with stereotactic radiosurgery, while the clinical outcome is improved with surgery followed by WBRT versus WBRT alone. However, due to their poor performance status, many patients with brain metastases are not eligible for surgery or radiosurgery. Furthermore, the role of systemic chemotherapy for the treatment of brain metastases is controversial due to the impenetrable nature of the blood brain barrier (BBB), with reported response rates to chemotherapy ranging from 15-30% (overall survival [OS] 6-8 months). Response rates of brain metastases to EGFR tyrosine kinase inhibitor (TKI) treatment (e.g. gefitinib, erlotinib, afatinib) in patients with NSCLC harboring EGFR mutations reach 60-80%, with a complete response rate as high as 40%. Median OS is 15-20 months, and progression-free survival in the brain reaches 6.6-11.7 months, demonstrating an improved clinical outcome. Metastatic involvement of the CNS appears to be a relatively common complication in patients with ALK-positive NSCLC and the CNS represents a dominant site of progression in ALK-positive patients treated with the ALK TKI crizotinib. In addition, CNS progression on crizotinib contributes substantially to the high levels of morbidity and mortality observed among patients with ALK-rearrangements, a finding that is consistent with low CNS penetration of the drug. Second-generation ALK inhibitors (ceritinib, alectinib) are well-tolerated and demonstrate excellent intracranial activity. The various reports of dramatic and prolonged responses in brain metastases patients treated with EGFR and ALK TKIs suggest that these agents may be a valid treatment option for patients with asymptomatic brain metastases from NSCLC, especially for those with EGFR-activating mutations or harboring ALK rearrangement. However, larger phase III studies are required to fully define the activity of these agents and their place in the therapeutic armamentarium of brain metastases.