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This is a prospective, multicenter, comprehensive genomic profile signature (GPS) study in paired tissue and plasma samples from 149 patients with advanced NSCLC harboring\n                    <jats:italic>EGFR<\/jats:italic>\n                    exon 19 deletion (Ex19del) or L858R mutation at the first-line treatment failure of osimertinib (NCT05219162). Next-generation sequencing (NGS) was used for comprehensive GPS analysis of paired tissue and plasma samples. Fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) were used for tissue samples, while droplet digital polymerase chain reaction (ddPCR) and NGS were used for plasma samples to perform a concordance analysis of\n                    <jats:italic>MET<\/jats:italic>\n                    amplification. At the first-line treatment failure of osimertinib (study entry),\n                    <jats:italic>EGFR<\/jats:italic>\n                    alterations in tissue samples included\n                    <jats:italic>EGFR<\/jats:italic>\n                    Ex19del (49.0%, 73\/149),\n                    <jats:italic>EGFR<\/jats:italic>\n                    L858R mutation (43.0%, 64\/149),\n                    <jats:italic>EGFR<\/jats:italic>\n                    amplification (32.9%, 49\/149),\n                    <jats:italic>EGFR<\/jats:italic>\n                    L718Q\/V mutation (4.7%, 7\/149), and\n                    <jats:italic>EGFR<\/jats:italic>\n                    C797S mutation (3.4%, 5\/149); bypass signaling activation and downstream pathway activation alterations included\n                    <jats:italic>TP53<\/jats:italic>\n                    mutation (69.8%, 104\/149) and\n                    <jats:italic>MET<\/jats:italic>\n                    amplification (30.9%, 46\/149). Among the 136 patients with\n                    <jats:italic>EGFR<\/jats:italic>\n                    Ex19del\/L858R mutation in tissue samples, 72.1% (98\/136), 35.3% (48\/136), and 32.4% (44\/136) had\n                    <jats:italic>TP53<\/jats:italic>\n                    mutations,\n                    <jats:italic>EGFR<\/jats:italic>\n                    amplification, and\n                    <jats:italic>MET<\/jats:italic>\n                    amplification, respectively. Taking tissue samples as references, the GPS in plasma samples showed high specificity (90.7\u2013100%) for almost all genomic alterations. Compared with FISH (gene copy number [GCN] \u226510), the overall percent agreement of tissue NGS, optimized tissue NGS (GCN\u2009\u2265\u20098.63), plasma NGS, and plasma ddPCR for\n                    <jats:italic>MET<\/jats:italic>\n                    amplification were 75.0% (27\/36), 100% (36\/36), 88.9% (32\/36), and 94.4% (34\/36), respectively. This study represents the largest-scale, prospective study with paired tissue and plasma samples to enable comprehensive analysis of GPS, providing a novel perspective into coalterations at the first-line treatment failure of osimertinib. A plasma sample serves as a supplement for identifying GPS when a tissue sample is unavailable. Moreover, the integration of FISH, NGS, and ddPCR provided a comprehensive assessment of\n                    <jats:italic>MET<\/jats:italic>\n                    amplification.\n                  <\/jats:p>","DOI":"10.1038\/s41392-025-02481-8","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T00:03:44Z","timestamp":1764633824000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["A prospective, multicenter, comprehensive genomic profile signature study in patients with EGFR-mutant advanced non-small cell lung cancer at the first-line treatment failure of osimertinib"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3342-4964","authenticated-orcid":false,"given":"Yuankai","family":"Shi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongqing","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weineng","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuoyan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Puyuan","family":"Xing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4137-2049","authenticated-orcid":false,"given":"Xiubao","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junqiang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaohua","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongchang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shundong","family":"Cang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enguo","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingxin","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,2]]},"reference":[{"key":"2481_CR1","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1056\/NEJMoa1713137","volume":"378","author":"JC Soria","year":"2018","unstructured":"Soria, J. 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