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This review summarizes the research progress of advances in small-molecule targeted agents against major driver oncogenes in NSCLC, including epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and Kirsten rat sarcoma viral oncogene homolog (KRAS). We elaborate on the mechanism of action, clinical efficacy and treatment-related adverse events (TRAEs) of each generation of inhibitors, while updating the developmental status of innovative therapies and emerging. Notably, this article further integrates clinical data of investigational small-molecule targeted drugs that address emerging oncogenic drivers such as rat sarcoma viral oncogene homolog (RAS), human epidermal growth factor receptor 2 (HER2), and v-src avian sarcoma viral oncogene homolog (SRC), which have demonstrated promising clinical activity in early-phase trials. These findings highlight potential avenues for future development of NSCLC-targeted therapies. Despite iterative optimization across multiple generations, current targeted drugs for NSCLC still face prominent limitations, including acquired drug resistance and insufficient penetration across the blood-brain barrier (BBB). Moving forward, future research should prioritize accelerating the clinical translation of investigational drugs, exploring combination treatment regimens, identifying novel molecular targets, and optimizing the overall system of molecular targeted therapy. These efforts will help further improve clinical outcomes for patients with NSCLC.<\/jats:p>","DOI":"10.3389\/fonc.2026.1847493","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T04:22:08Z","timestamp":1784089328000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Research progress of small molecule targeted drugs for non-small cell lung cancer"],"prefix":"10.3389","volume":"16","author":[{"given":"Tingxiang","family":"Qiu","sequence":"first","affiliation":[{"name":"College of Health Management, Shanghai Jian Qiao University","place":["Shanghai, China"]},{"name":"School of Medical College, Xi\u2019an Peihua University","place":["Xi\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Huang","sequence":"additional","affiliation":[{"name":"College of Health Management, Shanghai Jian Qiao University","place":["Shanghai, 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