We report a case of epidermal growth factor receptor (EGFR) wild-type advanced lung adenocarcinoma and review relevant literature. A 64-year-old female non-smoker was treated in a local hospital for no obvious cause of headache for 1 month. Chest CT showed a tumor in the right upper lung. Brain MR suggested multiple lesions in the brain, considering metastasis. Lung biopsy in our hospital indicated lung adenocarcinoma, plasma EGFR mutation test is negative. Because the patient refused to receive radiotherapy and chemotherapy, she was started on icotinib, progressive-free survival 14 months. After the front-line treatment failed, tumor tissue exon 20.pT790M mutation appeared. Third-denervation TKI Osimertinib was started and effective. For non-smoking Asian women with lung adenocarcinoma who cannot obtain tissue specimens or have negative EGFR mutation in plasma, targeted EGFR-TKIs therapy can be tried in patients who fail or are unsuitable for radiotherapy and chemotherapy, and some patients of those can benefit from it.