A 66-year-old man showed multiple bilateral nodules on chest radiography in 2003. A computed tomography revealed a tumor in the right upper lobe and multiple nodular shadows. He underwent right middle lobectomy and was diagnosed with adenocarcinoma (cT4N0M1, Stage IV), subsequently exhibiting EGFR mutation (exon 21 L858R). He was treated with six courses of carboplatin and paclitaxel in 2004, resulting in progressive disease. He was treated with gefitinib in 2005. He exhibited tumor progression after about 10 years; therefore, gefitinib was discontinued and pemetrexed administration was initiated. After 25 courses of pemetrexed therapy, we discontinued pemetrexed because he developed renal dysfunction. T790M was not detected in his liquid biopsy sample; therefore, gefitinib was re-started in 2017. Currently, he has been alive for 15 years after his diagnosis. Based on this case, we conclude that the re-administration of gefitinib can be considered when the activation of bypass pathway is possible.