Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in the Treatment of Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer Metastatic to the Brain

Brain metastases are a common and devastating consequence of disease progression in patients with non-small cell lung cancer (NSCLC). The epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib have shown efficacy in patients with NSCLC and brain metastases. The cerebrospinal fluid (CSF) exposure to these drugs is a small fraction of the plasma levels achieved with standard doses, but disruption of the blood-brain barrier in the presence of central nervous system metastases is likely to lead to locally increased drug concentration, and dose escalation to boost CSF exposure has documented clinical efficacy. The use of gefitinib and erlotinib in this setting is reviewed here, including evidence from case reports, case series, and single-arm phase II trials. High response rates in the brain are seen in patients with EGFR mutation, or in populations in which this genotype is expected. By contrast, activity in the context of documented wild-type EGFR in disease metastatic to the brain is not common. These drugs may potentiate the effectiveness of radiotherapy to the brain, and their use may also delay development of disease within the brain. Clin Cancer Res; 18(4); 938-44. (C) 2011 AACR.