In the non-small-cell lung cancer (NSCLC) subtype, adenocarcinoma is the most common histology. The choice of first-line treatment depends on the mutational status. We present a case of a 54-year-old non-smoker woman with lung adenocarcinoma and extensive metastatic disease at diagnosis. The genetic analysis demonstrated a sensitizing epidermal growth factor receptor (EGFR) exon 19 mutation and she began treatment with a first-generation EGFR tyrosine kinase inhibitor (TKI), erlotinib. Due to successively acquired resistances and disease progression, six treatment lines were pursued, including third-generation EGFR TKI and chemotherapy. The patient accomplished an overall survival of 47 months. This case emphasized the importance of monitoring tumor mutational alterations, allowing us to implement a multi-line treatment. Targeted therapy in advanced NSCLC largely improved the overall survival of these patients.