{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T12:10:02Z","timestamp":1785327002263,"version":"3.55.0"},"reference-count":174,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The discovery of activating epidermal growth factor receptor (EGFR) mutations transformed the management of non-small cell lung cancer and has driven two decades of therapeutic advances in precision oncology across metastatic, resectable, and unresectable locally advanced disease, including central nervous system (CNS) control. Consequently, treatment outcomes for patients with tumors harboring classical EGFR mutations have markedly improved. Despite these advances, many questions remain unanswered, and the expanding number of treatment options has created new challenges in treatment selection and sequencing. This narrative review summarizes contemporary data on the management of classical EGFR-mutant NSCLC, encompassing novel therapeutic approaches across disease stages, biomarker-informed resistance strategies, multimodality treatment integrating radiotherapy, CNS-directed management, and challenging scenarios such as small-cell transformation. We also discuss emerging fourth-generation inhibitors, nucleic-acid delivery platforms, and data-enabled personalized treatment. We highlight evolving standards of care, unresolved knowledge gaps, and research priorities for the next decade.<\/jats:p>","DOI":"10.3390\/cancers18152401","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:49:27Z","timestamp":1785131367000},"page":"2401","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Classical EGFR Mutations in Lung Cancer: Twenty Years of Progress and Beyond"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8047-8730","authenticated-orcid":false,"given":"Yuji","family":"Uehara","sequence":"first","affiliation":[{"name":"Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo 1040045, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5434-5459","authenticated-orcid":false,"given":"Hiroto","family":"Hatano","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo 1040045, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Tao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People\u2019s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiefei","family":"Han","sequence":"additional","affiliation":[{"name":"Cancer Center, Beijing Chest Hospital, Capital Medical University & Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin L. M.","family":"Chua","sequence":"additional","affiliation":[{"name":"Division of Radiation Oncology, National Cancer Centre Singapore, Singapore 168583, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3520-9464","authenticated-orcid":false,"given":"Stephanie P. L.","family":"Saw","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, National Cancer Centre Singapore, Singapore 168583, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1056\/NEJMoa040938","article-title":"Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non\u2013Small-Cell Lung Cancer to Gefitinib","volume":"350","author":"Lynch","year":"2004","journal-title":"N. Engl. J. 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