Epidermal growth factor receptor complex kinase inhibitors (EGFR-TKIs) are well known to us for significantly improving progression-free survival and quality of life in patients with non-small cell lung cancer (NSCLC) with EGFR-positive mutations, and it has been more than 15 years since the first-generation targeted drug, gefitinib, to the third-generation targeted drug, ametinib. The first generation of targeted drugs are reversible lung cancer targeted drugs, they are not firmly bound to the target and may separate after a period of binding. The drugs are: gefitinib, erlotinib, ectinib. Second-generation targeted therapy drugs are irreversible targeted therapy drugs that can bind to the target permanently. Compared with the first generation of targeted drugs, it can work on some rare targets. The drugs are: afatinib, dacotinib. The third generation of targeted therapy drugs, in addition to the common sensitive targets and rare targets, also acts on specific drug-resistant gene mutations. The drugs are: ositinib, amitinib, vorametinib.EGFR-TKIs not only block the EGFR pathway in tumors, but also in the skin and gastrointestinal tract, and cause related adverse events (AEs): diarrhea, hepatotoxicity, dermatological disorders, stomatitis, interstitial lung disease, and ophthalmotoxicity, which affect the quality of life of the patients as well as their drug adherence. Therefore, how to choose the first, second and third generation targeted drugs based on drug characteristics, efficacy and toxic side effects. First-generation drugs: gefitinib, erlotinib, ectinib Indications: Gefitinib: locally advanced or metastatic NSCLC with EGFR gene-sensitive mutations; erlotinib: locally advanced or metastatic NSCLC with EGFR gene-sensitive mutations; ectinib: (1) locally advanced or metastatic NSCLC with EGFR gene-sensitive mutations; (2) Stage II-IIIA NSCLC with EGFR gene-sensitive mutations. Sensitive mutation of EGFR gene; ② Postoperative adjuvant treatment of stage II-IIIA NSCLC with EGFR gene sensitive mutation. Gefitinib: the first generation of EGFR-TKIs is more likely to cause hepatotoxicity. Erlotinib: is the drug most likely to cause skin toxicity in first-generation EGFR-TKIs. Eketinib: the overall incidence of toxic side effects is low, and interstitial pneumonitis (ILD) is also rare in eketinib, but requires special attention. Second-generation drugs: afatinib, dacotinib Indications: Afatinib: ① locally advanced or metastatic NSCLC with sensitive mutations in the EGFR gene; ② locally advanced or metastatic squamous histologic type of NSCLC with disease progression during or after platinum-containing chemotherapy; ③ for locally advanced or metastatic NSCLC with non-classical mutations in the EGFR (e.g. L861Q, G719S, etc.). Dacotinib: locally advanced or metastatic NSCLC with sensitive mutations in the EGFR gene. Toxicities and side effects: There was no significant difference in the overall incidence of adverse effects (AEs) between afatinib and gefitinib, and the overall incidence of grade 3-4 AEs was higher for afatinib than for gefitinib (10.6% Vs 4.4%). The incidence of almost all treatment-related AEs, except for hepatotoxicity, was higher in dacotinib-treated patients than in gefitinib. Note: ① Afatinib and dacotinib can be reduced to continue treatment if they cannot tolerate toxic side effects. ② Data from the ARCHER1050 study showed that compared to the gefitinib group, the dacotinib group had prolonged progression-free survival (PFS) and overall survival (OS), making it the first EGFRTKI to provide clinically meaningful OS improvement. Third-generation drugs: ositinib, alectinib, and vorametinib Indications: ositinib: ① locally advanced or metastatic EGFR gene-sensitive mutated First-line treatment of NSCLC; ② Treatment of locally advanced or metastatic NSCLC patients who have disease progression during or after previous EGFR-TKI treatment and are confirmed to have EGFR-T790M mutation; ③ Postoperative adjuvant treatment for NSCLC patients with exon 19 deletion or exon 21 L858R replacement mutation in the EGFR gene of stage IB to IIIA, and the decision to receive or not receive adjuvant treatment should be made by the doctor. treatment, and the doctor decides to accept or not to accept adjuvant chemotherapy; ④ EGFR mutation-positive brain metastasis or meningeal metastasis patients are recommended to give priority to the use of ositinib. Amitinib: for the treatment of non-small cell lung cancer (NSCLC) with EGFR-sensitive mutations and EGFRT790M-resistant mutations. Vomitinib: for the treatment of non-small cell lung cancer (NSCLC) with EGFR-sensitive mutations and EGFRT790M-resistant mutations. Toxicities and side effects: Ositinib: Common adverse effects (AEs) are diarrhea, rash, dry skin, and onychomycosis. In addition, the incidence of grade ≥3 AEs was lower with ositinib compared to conventional EGFR-TKI therapy (32% vs 41%).The most notable AE with ositinib was prolongation of the electrocardiographic QT interval, which occurred at an incidence rate of 4.10%, and special attention should be paid to the development of interstitial pneumonitis. Amitinib: common adverse reactions are rash, elevated blood creatine phosphokinase, elevated aspartate aminotransferase, elevated alanine aminotransferase, and pruritus, etc. The incidence of diarrhea is relatively low. Vomitinib: Common adverse reactions are upper respiratory tract infection, cough, elevated alanine aminotransferase and/or aspartate aminotransferase, and prolonged QTc interval on ECG. Vigilance against interstitial pneumonitis is required. Many people think that after the first-generation targeted drugs are ineffective, the second- and third-generation targeted drugs are used sequentially. First-generation, second-generation and third-generation targeted drugs can be used for the initial treatment of locally advanced or metastatic NSCLC with EGFR gene-sensitive mutations; third-generation targeted drugs can also be used for patients with T790M drug-resistant gene mutations after receiving first- and second-generation targeted drug therapy. Among the various serious adverse reactions triggered by the treatment of first-, second-, and third-generation EGFR-TKIs, the third generation had the lowest incidence of serious adverse reactions, followed by the first generation, and the second generation had the highest incidence. Among first-, second-, and third-generation EGFR-TKIs, gefitinib was most likely to cause hepatotoxicity, and serious adverse reactions occurring in second-generation EGFR-TKIs could be minimized by dose reduction. Third-generation EGFR-TKIs have the longest PFS and OS for first-line treatment of NSCLC with EGFR-sensitive mutations.Third-generation agents have the highest blood-brain barrier permeability, which provides an advantage in the treatment of brain metastases or meningeal metastases. About 40% to 60% of patients who receive first- or second-generation EGFR-TKIs in first-line/initial therapy will develop T790M mutations after resistance and have the opportunity to be treated with third-generation EGFR-TKIs. Nowadays, EGFR-TKIs are in a state of blossoming and competition. Patients should choose the appropriate EGFR-TKIs drug based on drug efficacy, toxicity, availability and cost, as well as the patient’s financial resources. Putting aside the economic factors, third-generation EGFR-TKIs have the longest PFS and OS with the least toxic side effects.