We report a case of advanced lung adenocarcinoma with epidermal growth factor receptor sensitive mutation. The patient was a 60-year-old female with left lung adenocarcinoma T2aN2M0IIIA stage, and surgical specimens EGFR detection showed exon 19 mutation. After the operation, 4 courses of pemetrexed combined with cisplatin adjuvant chemotherapy were completed. In June 2016, the blood carcinoembryonic antigen was found to be 586.49 ng/mL. Further examination of PET-CT indicated lung cancer with mediastinal and right hilar lymph node metastasis, pleural metastasis, and multiple bone metastasis. First-line icotinib treatment lasted 15 months, with disease progression. In October 2017, a mutation of T790M was found in peripheral blood. Second-line osimertinib was treated for 12 months, and the disease progressed again. Pleural effusion second generation sequencing showed T790M disappeared, EGFR 19 exon mutation existed. The third line was treated with osimertinib and anlotinib. EFGR-TKI treatment can benefit PFS and safety in patients with EGFR-sensitive mutations. With the increase of treatment lines, the drug resistance mechanism is more complicated, and further research is needed to make individual treatment more precise.