Objective:To investigate the efficacy of osettinib in the treatment of first-line tyrosine kinase inhibitor-resistant advanced lung adenocarcinoma and its effects on carcinoembryonic antigen (CEA) and vascular endothelial growth factor (VEGF) levels.Methods:Seventy-two patients with first-line tyrosine kinase inhibitor-resistant advanced lung adenocarcinoma (T790M test negative or rejected) who received treatment in Jinhua Guangfu Cancer Hospital from June 2017 to June 2019 were included in this study. They were randomly assigned to undergo either conventional pemetrexed plus cisplatin (control group, n = 36) or osimertinib mesylate (observation group, n = 36) for 4 successive weeks. Before and after 4 weeks of treatment, serum CEA and VEGF levels were measured. Curative effects were evaluated. Adverse reactions and 6-month, 1-year and 2-year survival rate were recorded. Results:Effective rate and disease-control rate in the observation group were 80.6% (29/36) and 94.4% (34/36) respectively, which were significantly higher than 58.3% (21/36) and 75.0% (27/ 36) in the control group ( χ2 = 4.193, 5.261, both P < 0.05). Before treatment, there were no significant differences in serum CEA and VEGF levels between the two groups (both P > 0.05). Compared with before treatment, serum CEA and VEGF levels were significantly increased after treatment (both P < 0.05). After treatment, serum CEA and VEGF levels in the observation group were (5.36 ± 0.33) U/mL and (121.56 ± 11.57) ng/L respectively, which were significantly lower than those in the control group [(8.25 ± 0.54) U/mL, (163.68 ± 14.59) ng/L, t = 27.399, 13.572, both P < 0.001]. The incidence of adverse reactions in the observation group was significantly lower than that in the control group [19.4% (7/36) vs. 44.4% (16/36), χ2 = 5.173, P = 0.011]. 6-month, 1-year and 2-year survival rate were 94.29%, 77.14% and 60.00% respectively, in the observation group and 91.43%, 54.29% and 34.29% respectively in the control group. There was no significant difference in 6-month overall survival rate between the two groups ( χ2 = 0.352, P = 0.251). 1-year and 2-year survival rate in the observation group were significantly higher than those in the control group ( χ2 = 4.058, P = 0.044; χ2 = 4.644, P = 0.031). Conclusion:Ositinib is effective in the targeted treatment of first-line tyrosine kinase inhibitor-resistant advanced lung adenocarcinoma. It can effectively decrease serum CEA and VEGF levels and prolong the survival of patients, thereby exhibiting a clinical application value.