Lung cancer patients are mostly diagnosed with metastases and chemotherapy used to be the only effective way to prolong patient survival, but the development of targeted therapies has turned this status upside down. Most driver mutations are mutually exclusive, with only one of them present in each NSCLC patient. Targeted drug inhibition of drivers can induce significant tumor responses, resulting in higher response rates and longer patient disease-free and overall survival than traditional cytotoxic drugs. Current targeted driver mutations include the common EGFR mutations, KRAS mutations, ALK translocations, and the less common ROS1 translocations, RET translocations, BRAF mutations, HER2 mutations, NTRK translocations, MET amplifications or mutations. The percentage of driver mutations in lung adenocarcinoma was approximately: EGFR 15%, KRAS 25%, ALK 7%, HER2 2%, BRAFV600E 2%, ROS1 2%, RET 2%, NTRK1 0.5%, MET 3%, MAP2K1 0.5%, PIK3CA 1%, and NRAS 0.5%. The proportion of driver mutations in squamous cell carcinoma was approximately: EGFR 5%, DDR2 4%, FGFR1 17%, PIK3CA 14%, PTEN 18%, PDGFRA 9%, and FGFR2 3%. 1. Common driver mutations (1) EGFR mutations Several large phase III clinical trials have confirmed that EGFR tyrosine kinase inhibitors (TKI) are more effective than chemotherapy in treating EGFR mutation-positive NSCLC, and therefore almost all guidelines recommend EGFR TKI (e.g., gefitinib, erlotinib, afatinib) as the first-line treatment option for EGFR mutation-positive NSCLC. The study Studies have shown that patients with EGFR mutations at different loci respond differently to different EGFR TKI’s, with afatinib significantly improving OS in patients with EGFR mutations in exon 19 (del19) compared to conventional chemotherapy, but not in exon 21, while patients with insertional mutations in exon 20 are not sensitive to all EGFR TKI’s currently on the market Patients with exon 20 insertional mutations were not sensitive to all currently available EGFR TKI. The study also showed that the efficacy of afatinib appeared to be slightly better than gefitinib, with median PFS of 11.0 and 10.9 months, respectively, and HR of 0.73. Therefore, drug selection should take into account the patient’s physical status, ease of treatment, and adverse effects, such as the greater susceptibility to hepatotoxicity with gefitinib and diarrhea and skin toxicity with afatinib. To improve efficacy, studies have also attempted to combine EGFR TKI with cytotoxic agents or bevacizumab, showing that erlotinib in combination with bevacizumab significantly improves PFS in EGFR mutation-positive patients compared to erlotinib alone. Although EGFR TKI alone has maintained good outcomes in some patients for many years, almost all patients eventually develop disease due to acquired drug resistance progression. In addition, studies have shown that continued use of gefitinib after disease progression in patients treated with gefitinib in combination with platinum-based chemotherapy does not prolong PFS, and therefore the combination of TKI and chemotherapy is not recommended. In clinical practice, chemotherapy is often used in the setting of acquired resistance to TKI therapy. For patients who develop oligoprogression after EGFR TKI therapy alone, local radiotherapy or surgical resection combined with EGFR TKI is recommended for continued treatment. (2) KRAS mutations KRAS mutations are the most common driver mutations in lung cancer, but the development of targeted drugs for them is not promising. there are many different types of KRAS mutations, and they may stimulate different downstream pathways. In addition, KRAS mutations are associated with mutations in TP53, STK11, CDKN2A/B, etc. Tumors with different co-mutations have different gene expression patterns, such as an epithelial phenotype with high expression of ERBB3 and E-cadherin, or a mesenchymal phenotype with high expression of wave proteins, FGFR1 and FRS2, and tumors with different phenotypes may require different treatments. Preclinical studies have shown that fibroblast growth factor receptor (FGFR) antagonists can inhibit drug resistance to trametinib and are effective in lung cancers with KRAS mutations, particularly in the mesenchymal phenotype. Combining MEK and CDK4 inhibitors, or CHK1 and MK2 inhibitors has also shown good efficacy in preliminary trials. (3) ALK translocation In 2007, statistics showed that about 3%-5% of NSCLC had translocation of the mesenchymal lymphoma kinase (ALK) gene. Studies have shown that crizotinib significantly prolongs PFS in ALK-positive lung cancer patients, and thus crizotinib has been approved for treatment of lung cancer patients in the United States, Europe and Japan. However, resistance to crizotinib cannot be ignored, and the most important resistance mechanism is ALK secondary mutations, which are known to include 1151Tins, Leu1152Arg, Cys1156Tyr, Ile1171Thr, Phe1174Leu, Val1180Leu, Leu1196Met, Gly1202Arg, Ser1206Tyr, and Gly1206Tyr. Ser1206Tyr and Gly1296Ala. More complete data are still needed to determine whether the current novel ALK inhibitors can be used as first-line treatment or second-line treatment after crizotinib resistance. 2. Uncommon driver mutations To improve the prognosis of NSCLC patients without EGFR mutations or ALK translocations, investigators have identified a number of novel driver mutations as therapeutic targets. (1) ROS1 translocations are present in approximately 1% to 2% of patients with NSCLC, predominantly in adenocarcinoma, young patients, and nonsmokers. Crizotinib has been approved by the FDA for the treatment of ROS1-positive NSCLC patients. ROS1 inhibitors such as ceritinib and cabozantinib are still in clinical trials. (2) RET translocations are present in about 1%-2% of NSCLC patients and are more common in nonsmokers, young adenocarcinoma or squamous carcinoma patients. Multi-target TKI are effective against RET kinase, such as vandetanib, cabozantinib, aretinib hydrochloride, apatinib, etc. They are currently in phase 1 or 2 clinical trials. (3) BRAF mutation BRAF is an important signaling molecule downstream of KRAS, which can activate MAP kinase pathway. BRAF inhibitors can compensate for the increase in RAS signaling, therefore, we investigated the efficacy of BRAF inhibitors in combination with MEK inhibitors and showed that the response rate of BRAFV600E mutation positive lung cancer patients was higher than that of non-BRAFV600E mutation positive lung cancer patients. Further studies are needed for the treatment of patients with BRAFV600E mutation. (4) HER2 mutations are present in 1% to 2% of NSCLC patients, and are more common in women, nonsmokers and adenocarcinoma. The effectiveness of targeted therapies for HER2 mutations is controversial and needs to be further investigated. In addition to the above mutations, NTRK translocations and MET amplifications or mutations are also seen in lung adenocarcinoma, while driver mutations in squamous cell carcinoma are less commonly reported and currently known include FGFR1 amplifications and DDR2 mutations. Important molecules related to tumor cell proliferation and survival include EGFR monoclonal antibodies and anti-angiogenic agents: EGFR signaling pathway plays an important role in lung cancer formation, EGFR protein is widely expressed in bronchial dysplasia, and overexpression and activation of EGFR is seen in squamous cell carcinoma. Studies have shown that EGFR monoclonal antibody improves overall survival in squamous cell carcinoma, and Necitumumab has been approved by the FDA and EMA for the treatment of patients with advanced squamous carcinoma. VEGF is a major regulator of angiogenesis, and increased expression of VEGF often indicates poor prognosis. VEGF receptor antagonists have shown good efficacy in clinical trials, and ramucirumab has been approved by the EMA and FDA for clinical treatment. The relationship between tumor cells and the tumor microenvironment has received increasing attention in recent years, especially the molecular mechanisms by which tumor cells evade immune surveillance, i.e., immune escape. Immune-targeted therapies that inhibit immune escape have been shown to be effective in advanced NSCLC. Inhibitory checkpoint molecules are currently the most common targets of immunotherapy, including cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed death receptor 1 (PD-1) and its ligand (PD-L1). PD-L1 or PD-L2 can also inhibit T-cell activation by binding to PD-1 on the surface of T cells. Anti-CTLA-4, PD-1 and PD-L1 antibodies have shown promising efficacy in a variety of cancers, and nabumab and pabumumab have been approved by the FDA and EMA for use in patients with advanced NSCLC.