The first-line use of TKI-based targeted drugs in lung cancer patients with EGFR-sensitive mutations has now become a standard treatment option. Meanwhile, it is widely popular in the clinic because of its good efficacy, long remission time, and small toxic side effects. However, even if the efficacy is good in the early stage, drug resistance, i.e. acquired drug resistance, will inevitably occur in the later stage. How to solve the acquired resistance of EGFR-TKI has become the focus and difficulty of research in recent years. The professor summarized the follow-up treatment strategy of EGFR-TKI acquired resistance in the following two directions. 1.Delaying TKI acquired resistance A large number of retrospective studies in recent years have shown that RESIST evaluation of PD is not an indication for discontinuation of TKI drugs. As long as the patient’s general condition is still good and the disease progresses slowly, the patient can still continue TKI treatment and still benefit from it, significantly prolonging PFS, generally prolonging the time of about 2-3 months, and this conclusion has also been verified in the ASPIRATION prospective clinical study. At the same time, we must be clear about the timing of TKI discontinuation, i.e., change of treatment regimen: 1) the appearance of new metastatic lesions, especially the appearance of extensive metastatic lesions; 2) a significant worsening of symptoms associated with the disease; 3) rapid tumor growth. In particular, it should be noted that the evaluation of PD due to new brain metastases is not a criterion for TKI treatment failure, nor is it an indication for TKI discontinuation, mainly because of the presence of the blood-brain barrier. In this group of patients, we can continue TKI therapy along with localized treatment of brain metastases. Retrospective studies have shown that continuing TKI therapy in these patients can extend the clinical benefit by 7-10 months. In addition, for patients with EGFR-sensitive mutations, we can give them first-line treatment: 1) Targeted drug + targeted drug: erlotinib + bevacizumab, the results of the preliminary study showed that the PFS was prolonged by 6.3 months compared with single-agent erlotinib, but the OS results are still worthy of expectation; 2) Sequential or synchronous chemotherapy with targeted drug: clinical studies such as FASTACT-2, NEJ005, JMIT, etc. have reached a positive answer, regardless of the PFS, we can give patients with EGFR-sensitive mutations the same TKI treatment. The clinical studies such as FASTACT-2, NEJ005, JMIT, etc. all gave a positive answer, both in PFS and OS, compared with TKI alone or chemotherapy alone, with obvious improvement. However, the above clinical studies are basically phase II clinical studies, and we still need phase III clinical studies to verify them. The above treatment strategies allow us to maximize the use of TKI analogues to maximize their efficacy. The duration of TKI treatment has been extended. 2.Treatment strategy after drug resistance If the disease progresses rapidly and requires a complete replacement of the treatment plan, what treatment methods can be used for reference: Strategy 1: second-line replacement with chemotherapy. the results of the IMPRESS study have long shown that there is no prolongation of PFS after secondary resistance to TKI by continuing to target drugs while combining chemotherapy with chemotherapy alone. Therefore, the consensus of the 12th Lung Cancer Summit Forum on EGFR-TKI acquired resistance clearly pointed out that the use of TKI combined with chemotherapy is not recommended after EGFR-TKI secondary resistance. It also pointed out that if replaced with chemotherapy, it is recommended to choose Lipitor. However, the recent subgroup analysis showed that there was a 1.3-month improvement in the PFS of those with T790M(-), while there was no prolongation of the PFS of those with T790M(+), and even a decrease of 0.7 months. This suggests that subsequent treatment of T790M(-) patients with secondary resistance may provide a mild benefit by continuing with a generational TKI in combination with chemotherapy. Another retrospective study has shown that Re-treatmentwithTKI (i.e., second-line replacement with chemotherapy after failure of TKI therapy, and continuation of TKI therapy after progression of chemotherapy), showed a slight improvement in OS and PFS. However, this study is a retrospective study and still needs to be validated by a phase II prospective clinical study. Strategy 2: Application of second-generation targeted drug afatinib. The large phase III clinical studies LUX-LUNG1 to LUX-LUNG5 have demonstrated to us that the second-line application of the second-generation TKI afatinib treatment had a benefit of more than 2 months in PFS compared with the placebo group, but there was no improvement in OS. Therefore, second-line application of second-generation TKI alone may not be wise. Another phase II clinical study, in which second-line afatinib + cetuximab was given to first-line TKI-resistant patients, showed that it was effective in both T790M (+) and (-) patients, with PFS up to almost 5 months. However, it is conceivable that the combination of these two drugs has a large number of side effects, which few patients can tolerate, especially skin rash, and no OS results. Therefore, second-generation TKIs did not show significant advantages in secondary resistance. Strategy 3: Application of third-generation TKI analogs AZD9291 and CO1686. This is also the most popular direction of current research.T790M mutation is a point mutation on exon 20 of EGFR, which is the most common mutation mechanism known for TKI acquired resistance. Several phase II-III clinical studies have shown that after TKI secondary resistance with T790M(+), the patient will take a very good clinical outcome, with an ORR of about 70% and a PFS of more than 4 months. The dose comparison study showed that the high dose group did not bring more obvious ORR and PFS, thus indicating that the appropriate dose is more clinically significant than the maximum tolerated dose in the era of targeted drug therapy. Strategy 4: Immunotherapy. Pre-exploratory clinical studies showed that erlotinib + PD-1 monoclonal antibody Nivolumab could achieve an RR of 19% and a PFS of 24 weeks, but this result was not significantly different from the pre-exploratory studies with PD-1 alone with an RR of 15%-25%. Therefore, single-agent PD-1 monoclonal antibody may be more suitable for clinical use. We now advocate precision therapy, which is needed not only in the initial stage of treatment, but also after the development of secondary resistance, but at this time precision therapy becomes more difficult, because a large number of preliminary studies have shown that the heterogeneity of tumors will become more obvious after targeted therapy, and different mechanisms of resistance will appear in different metastatic sites, and different mutations will occur, while the peak of various mutated genes is also The peaks of various mutated genes are also different. Therefore, we still have a long way to go in the treatment of secondary drug resistance.