Objective: To explore the feasibility and clinical effects of the combination of Anlotinib and Ecetinib in the treatment of patients with epidermal growth factor receptor(EGFR) 21 exon L858R mutation in lung adenocarcinoma with brain metastasis. Methods: Patients with advanced lung adenocarcinoma and multiple brain metastases admitted to our hospital from January, 2021 to December, 2023 were selected as out study subjects. 101 patients with EGFR21 exon L858R mutation were screened out by high-throughput sequencing(NGS) gene testing. The patients were randomly divided it into control group(n=51) and observation group(n=50). Patients in the control group received Ecetinib treatment while patients in the observation group received Anlotinib combined with Ecetinib.The effect of the treatment in the two groups were compared. Results: After treatment, the objective response rate(ORR) of the observation group was 76.00%, which was higher than 50.98% of the control group, and the difference was statistically significant(P<0.05).There was no statistically significant difference(P>0.05) in disease control rate(DCR) between the two groups.Before treatment, there was no statistically significant difference in the levels of tumor markers between the two groups(P>0.05).After the treatment, the average levels of carbohydrate antigen 125(CA125), carcinoembryonic antigen(CEA), tissue polypeptide antigen(TPA), and thymidine kinase 1(TK1) in the two groups were lower than those before treatment with statistical significance(P<0.05).In addition, the average levels of CA125, CEA, TPA and TK1 in the observation group were lower than those in the control group with statistical significance(P<0.05).Before treatment, there was no statistically significant difference in the length and diameter of brain tumors between the two groups(P>0.05), but after treatment, the length and diameter of tumors in the observation group were shorter than those in the control group, and the difference was statistically significant(P<0.05).Before treatment, there was no significant difference in various scores of life quality between the two groups(P>0.05).After treatment, the scores of physical, role, cognitive, psychological, and social functions in both groups were higher than those before treatment with statistical significance(P<0.05).In addition, the scores of physical, role, cognitive, psychological and social functions in the observation group were higher than those in the control group with significant differences(P<0.05).After treatment, there was no significant difference in the incidence of adverse reactions such as bone marrow transplantation, gastrointestinal reactions, rash, and hypertension between the two groups(P>0.05). Conclusion: The combination therapy of Enrotinib and Exetinib not only effectively inhibits the growth and metastasis of lung adenocarcinoma patients with EGFR21 exon L858R mutation and brain metastasis, but also significantly reduces the level of tumor markers, thereby promoting the improvement of patients' quality of life.The treatment regimen is safe and doesn't increase the risk of adverse reactions.