As we all know, the treatment of lung cancer has gone from clinical symptoms to histopathology, and nowadays to molecular level, the treatment mode of the disease is becoming more and more refined and individualized, and more emphasis is placed on the selection of targeted drugs based on patient-specific mutated genes to improve the efficacy, survival and prognosis. Professor Enriqueta Felip reported that the mutation rate of KRAS gene is the highest (26.9%), followed by EGFR (9.4%). In addition, other common mutated genes include PIK3CA (2.6%), RET (1.9%), ROS (1.7%), BRAF (1.6%), and HER-2 (0.9%). Currently, targeted therapies for the following targets have entered the clinic: i. EGFR For the first-line treatment of EGFR mutation-positive patients, the available small molecule inhibitors are gefitinib, afatinib and erlotinib. EGFR-TKI significantly improves the progression-free survival (PFS) of patients compared to conventional platinum-containing double agents. As research progressed, it was found that the difference in efficacy was significant by EGFR mutation type. One study found that afatinib significantly improved overall patient survival (OS) compared to conventional chemotherapy in the del19 EGFR mutation subgroup, while in the L858R mutation subgroup, the difference in patient outcomes was not significant. In a similar study, a randomized, open phase II clinical study comparing the efficacy of erlotinib in combination with or without bevacizumab in EGFR mutation-positive patients found a significant delay in PFS in the combination group (16.0 vs. 9.7 months, P=0.0015); while subgroup analysis showed that the PFS ratio in the del19 EGFR mutation subgroup versus the L858R mutation subgroup was were 18.0 vs 10.3 months and 13.9 vs 7.1 months, respectively. Although the emergence of EGFR-TKI has greatly encouraged investigators’ confidence, the subsequent emergence of drug resistance has become a new “roadblock”, with most patients developing acquired drug resistance after one year of EGFR-TKI use. In recent years, there have been many studies on the mechanism of EGFR resistance, summarized in two points, namely, specific mutation of EGFR gene (about 60%) and bypass activation of MET, HER-2 and other genes (20%). EGFR-specific gene mutations are mainly T790M (40%-55%), and the New England Journal published data from two preliminary studies of the T790M inhibitors Rociletinib and AZD9291 in patients with non-small cell lung cancer who progressed on first-line EGFR-TRI therapy, showing that Rociletinib in T790M-positive patients with a response rate (RR) of 59%, compared to 29% in negative patients. Similarly, AZD9291 had a response rate of 61% vs. 21% in both. C-MET amplification is also a cause of EGFR-TKI resistance, and a study published in last year’s ASCO showed results from a phase II study of the MET inhibitor INC280 versus gefitinib in patients with dual positive EGFR mutations and MET amplification. this target has some therapeutic promise for EGFR-TKI-resistant patients. Second, ALK For patients with positive ALK mutations crizotinib is preferred, and a study published in the New England Journal in 2014 showed that in ALK mutation-positive patients, crizotinib significantly improved patients’ PFS and quality of life compared with a two-drug chemotherapy regimen. And if the use of crizotinib after progression, second-line ALK inhibitors are Ceritinib and Alectinib. in addition to this, more and more ALK inhibitors began to enter clinical trials, including birgatinib, PF-06463922, etc. With the release of the results of various studies, it is believed that the use of ALK inhibitors will become more and more mature. Third, ROS1 Research on ROS1 is still relatively early. In 2014, the New England Journal published the results of a phase I clinical study of crizotinib in patients with advanced non-small cell lung cancer, enrolling a total of 50 patients with a response rate of 72% and a median PFS of 19.2 months; in terms of safety, the toxic side effects of crizotinib were similar to those in patients with ALK rearrangement. In addition, in 2015 JCO published the results of a retrospective analysis of crizotinib in patients with ROS1-mutated IV lung adenocarcinoma, with a response rate of 80% and median PFS of 9.1 months in 32 patients, and these results suggest that crizotinib is a possible option for patients with ROS1 mutation-positive disease. Regarding the ROS1 target, other relevant ongoing studies include the detection of the ROS1 gene in circulating tumor cells and the use of Cabozantinib , ceritinib and PF-06463922 for the therapeutic evaluation of ROS1 patients after crizotinib resistance. IV. HER-2 The initial exploration for HER-2 targets are: afatinib, currently in a phase II clinical study ETOP; trastuzumab, the results of a clinical study published by JCO in 2015 showed that trastuzumab had a better response rate in HER-2-positive patients; Neratinib, a study published by ESMO in 2014 comparing the efficacy of Neratinib with or without temsirolimus in patients with non-small cell lung cancer with HER-2 mutation, showed that 54% of 13 patients in the single-agent group had SD, 46% PD, and a median PFS of 2.9 months; of 14 patients in the combination group, 21% were complete patients, 79% were stable, and the median PFS was 4.0 months, thus Neratinib combined with temsirolimus has some therapeutic value for HER-2 positive patients, of course, we still need further clinical trials to confirm. V. BRAF BRAF mutation rate in patients with advanced lung adenocarcinoma is about 2.2%, most of which are V600E mutations. 2015 JTO journal published the results of a phase I study on vemurafenib, dabrafenib and sorafenib in a European population of patients with advanced lung adenocarcinoma with BRAF mutations. The study found a V600E mutation rate of 83% and a response rate of 53% in 35 patients, while the OS ratio in the V600E mutation-positive group versus the negative group was 25.3 vs. 11.8 months. Another phase II clinical result evaluating the efficacy of dabrafenib in patients with BRAF-mutated advanced lung adenocarcinoma showed a disease control rate of 51% and a median PFS of 5.5 months. A preliminary phase II clinical study evaluating the efficacy of dabrafenib in combination with the MEK inhibitor trametinib in patients with BRAF-mutated advanced lung adenocarcinoma showed that dabrafenib in combination with trametini had some antitumor effects in patients with BRAF-mutated advanced lung adenocarcinoma with a controlled safety profile. Sixth, the MET A8081001 study showed that the response rate of crizotinib in patients with MET mutated non-small cell lung cancer was about 67%, and the Acse trial also showed that the ORR of crizotinib in patients with MET mutated non-small cell lung cancer was 32% and the DCR was 60%, which indicates that crizotinib has certain efficacy against this target. In conclusion, with the progress of the times, more and more targets are gradually coming onto the lung cancer stage, and it is believed that along with the efforts of researchers around the world, the treatment of advanced lung cancer will gradually achieve precision and individualized treatment, which is not only a gospel for clinical and scientific researchers, but also a hope for lung cancer patients.