A 65-year-old female, never smoker, with advanced non-small cell lung cancer (NSCLC) was admitted to the Kecheng District People’s Hospital of Quzhou, Zhejiang Province. The patient denied a family history of cancer. Due to a 13-year surgery history of the right lower lung cancer, the patient wanted to conduct a review. Enhanced chest CT showed multiple malignant tumors in both lungs, the largest layer of the left upper lobe was about 3.6 cm ×3.2 cm, the largest part of the right lung was about 5.9 cm ×3.5 cm, and the left flank was expansive bone destruction. Enhanced cranial MRI showed abnormal enhancement of bilateral temporal lobe (about 0.5 cm ×0.5 cm), indicating metastasis. The pathology of left lung puncture was NSCLC and prone to adenocarcinoma. In the further immunohistochemistry study, the results demonstrated CK7 (+), napsin-A (+), TTF-1 (+), p40 (−), p63 (−), Ki-67 (5%+). The genetic testing of tissue identified a common EGFR mutation (E19del). Based on the above results, “gefitinib (Iressa)” was initiated as the first-line treatment. The lung lesions were significantly reduced and the intracranial lesions disappeared during gefitinib therapy. However, the disease progressed after 16 months and a novel EGFR mutation (T790M) was detected. Hence, the patient acquired another targeted therapy with “oxitinib mesylate (Terisha)”, and the disease continues to be relieved.