{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T05:06:11Z","timestamp":1789103171746,"version":"build-2803163510"},"reference-count":51,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Cancer Control"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:p>In this narrative review, we examine baseline uncommon epidermal growth factor receptor (EGFR) mutations in non\u2013small-cell lung cancer (NSCLC) through a structure\u2013function classification framework and clinical evidence interpretation. Baseline uncommon EGFR mutations are molecularly heterogeneous, and exon-based classification alone cannot fully capture their structural diversity or variable sensitivity to EGFR-targeted therapy. By relating kinase-domain conformation to therapeutic sensitivity, structure\u2013function classification offers a biologically grounded lens for interpreting this heterogeneity alongside sequence-based classification. This review focuses on baseline uncommon EGFR mutations, including EGFR exon 20 insertion (ex20ins) mutations, P-loop and \u03b1C-helix\u2013compressing (PACC) mutations, and classical-like and long-tail non-ex20ins variants, while distinguishing them from acquired resistance alterations after EGFR tyrosine kinase inhibitor (EGFR-TKI) exposure. Typical loop-region ex20ins mutations can impose steric constraints near the ATP-binding pocket and are generally associated with limited activity of conventional EGFR-TKIs. Among ex20ins-directed approaches, amivantamab plus carboplatin\u2013pemetrexed chemotherapy is supported by mature randomized first-line evidence in approved and accessible settings; oral ex20ins-directed EGFR-TKIs require interpretation according to treatment line, regulatory context, study design, and follow-up maturity. For PACC mutations, EGFR-TKI activity has been reported mainly in selected recurrent variants, whereas evidence remains uneven across agents, variants, compound mutations, and less common PACC-related alterations. Among classical-like and long-tail non-ex20ins variants, L861Q illustrates how clinically defined cohorts may combine mutations with distinct structural and pharmacologic profiles, whereas long-tail alterations remain dependent on limited variant-level evidence. Overall, the evidence base remains heterogeneous, spanning randomized trials, single-arm studies, retrospective cohorts, real-world datasets, conference abstracts, and early clinical reports. Taken together, the evidence supports a structure-informed approach to baseline uncommon EGFR-mutant NSCLC, while treatment interpretation and clinical application should remain grounded in evidence level, clinical context, and treatment availability. Prospective subtype-stratified studies, consistent evidence grading, and standardized molecular reporting with structure-informed annotations are needed to improve clinical interpretation and inform treatment strategies.<\/jats:p>","DOI":"10.1177\/10732748261481943","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T04:49:35Z","timestamp":1788929375000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Baseline Uncommon EGFR Mutations in Non\u2013Small-Cell Lung Cancer: Structure\u2013Function Classification and Clinical Evidence Interpretation"],"prefix":"10.1177","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9752-1699","authenticated-orcid":false,"given":"Susu","family":"Yang","sequence":"first","affiliation":[{"name":"Graduate School of Qinghai University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuqin","family":"Ma","sequence":"additional","affiliation":[{"name":"Graduate School of Qinghai University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongwei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Graduate School of Qinghai University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0664-8086","authenticated-orcid":false,"given":"Jinhua","family":"Ma","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Qinghai University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"e_1_3_7_2_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"e_1_3_7_3_2","doi-asserted-by":"publisher","DOI":"10.4065\/83.5.584"},{"key":"e_1_3_7_4_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.70024"},{"key":"e_1_3_7_5_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.12587"},{"key":"e_1_3_7_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canep.2021.102080"},{"key":"e_1_3_7_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2024.03.016"},{"key":"e_1_3_7_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03898-1"},{"key":"e_1_3_7_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(15)00026-1"},{"key":"e_1_3_7_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3007205"},{"key":"e_1_3_7_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmoldx.2016.10.002"},{"key":"e_1_3_7_12_2","doi-asserted-by":"publisher","DOI":"10.5858\/arpa.2017-0388-CP"},{"key":"e_1_3_7_13_2","doi-asserted-by":"publisher","DOI":"10.1186\/s41073-019-0064-8"},{"key":"e_1_3_7_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2018.06.019"},{"key":"e_1_3_7_15_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.Mct-12-0620"},{"key":"e_1_3_7_16_2","doi-asserted-by":"publisher","DOI":"10.1097\/JTO.0b013e3182779d18"},{"key":"e_1_3_7_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cllc.2021.04.009"},{"key":"e_1_3_7_18_2","doi-asserted-by":"publisher","DOI":"10.3760\/cma.j.cn112152-20230905-00125"},{"key":"e_1_3_7_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtocrr.2020.100051"},{"key":"e_1_3_7_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-17394-7"},{"key":"e_1_3_7_21_2","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2022.0025"},{"key":"e_1_3_7_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2020.03.014"},{"key":"e_1_3_7_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2018.08.668"},{"key":"e_1_3_7_24_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2306441"},{"key":"e_1_3_7_25_2","unstructured":"U.S. Food and Drug Administration. 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