{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:07:31Z","timestamp":1790082451314,"version":"4.0.1"},"reference-count":27,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    In advanced non\u2010squamous non\u2010small cell lung cancer (non\u2010sq NSCLC), companion diagnostic testing (CDx) identifies actionable driver alterations and guides initial targeted therapy. However, disease progression inevitably occurs through acquired resistance, including activation of bypass signaling pathways. Although comprehensive genomic profiling (CGP) can identify emerging resistance alterations, its clinical utility in patients with known actionable driver alterations remains unclear. We retrospectively analyzed 227 patients who underwent CGP between June 2019 and August 2025. Patients with actionable driver alterations identified by CDx before CGP formed the known driver group. We also analyzed the nationwide C\u2010CAT registry to assess registry\u2010recorded therapeutic implementation. Among 227 patients, 74 (32.6%) had known actionable driver alterations. CGP identified additional clinically relevant genomic findings, including ESCAT Tier I\u2013III or V alterations, in 34 patients (45.9%), comparable to that in patients without known actionable driver alterations (77\/153, 50.3%). In the\n                    <jats:italic>EGFR<\/jats:italic>\n                    \u2010mutated (\n                    <jats:italic>EGFR<\/jats:italic>\n                    m) subgroup, CGP frequently identified alterations consistent with potential bypass resistance mechanisms, including\n                    <jats:italic>MET<\/jats:italic>\n                    amplification,\n                    <jats:italic>RET<\/jats:italic>\n                    fusions, and\n                    <jats:italic>BRAF<\/jats:italic>\n                    V600E mutations. Overall, 10 patients (13.5%) received CGP\u2010guided therapy based on additional findings, all within the\n                    <jats:italic>EGFR<\/jats:italic>\n                    m subgroup, whereas no patients with non\u2010\n                    <jats:italic>EGFR<\/jats:italic>\n                    driver alterations did. In the C\u2010CAT registry, CGP\u2010associated therapy was documented in 21 of 381 (5.5%) in the\n                    <jats:italic>EGFR<\/jats:italic>\n                    m subgroup, 6 of 155 (3.9%) in the non\u2010\n                    <jats:italic>EGFR<\/jats:italic>\n                    driver subgroup, and 195 of 2132 (9.1%) without registry\u2010defined driver alterations. These findings indicate that CGP provides molecular re\u2010evaluation during disease progression, particularly by identifying alterations consistent with potentially actionable resistance or bypass mechanisms in\n                    <jats:italic>EGFR<\/jats:italic>\n                    m NSCLC.\n                  <\/jats:p>","DOI":"10.1111\/cas.70538","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T12:22:06Z","timestamp":1790079726000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comprehensive Genomic Profiling Beyond Driver Testing in Non\u2010Squamous Non\u2010Small Cell Lung Cancer With Known Drivers"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2886-6638","authenticated-orcid":false,"given":"Yoshihiro","family":"Masui","sequence":"first","affiliation":[{"name":"Department of Thoracic Oncology National Cancer Center Hospital  Tokyo Japan"},{"name":"Division of Genome Biology National Cancer Center Research Institute  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4896-5824","authenticated-orcid":false,"given":"Tatsuya","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoh","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Miyakoshi","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoko Inaba","family":"Higashiyama","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Tateishi","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Shinno","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Endoscopy, Respiratory Endoscopy Division National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Okuma","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomonori","family":"Mizutani","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9090-801X","authenticated-orcid":false,"given":"Hidehito","family":"Horinouchi","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5821-7400","authenticated-orcid":false,"given":"Kouya","family":"Shiraishi","sequence":"additional","affiliation":[{"name":"Division of Genome Biology National Cancer Center Research Institute  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5371-706X","authenticated-orcid":false,"given":"Takashi","family":"Kohno","sequence":"additional","affiliation":[{"name":"Division of Genome Biology National Cancer Center Research Institute  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5807-8458","authenticated-orcid":false,"given":"Takafumi","family":"Koyama","sequence":"additional","affiliation":[{"name":"Department of Experimental Therapeutics National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0787-2851","authenticated-orcid":false,"given":"Noboru","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology National Cancer Center Hospital  Tokyo Japan"},{"name":"Department of Experimental Therapeutics National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7437-5054","authenticated-orcid":false,"given":"Yasushi","family":"Goto","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology National Cancer Center Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"issue":"1","key":"e_1_2_14_2_1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41572-024-00551-9","article-title":"Non\u2010small\u2010cell lung cancer","volume":"10","author":"Hendriks L. E. L.","year":"2024","journal-title":"Nature Reviews. Disease Primers"},{"issue":"4","key":"e_1_2_14_3_1","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.annonc.2022.12.009","article-title":"Oncogene\u2010Addicted Metastatic Non\u2010Small\u2010Cell Lung cancer: ESMO Clinical Practice Guideline for Diagnosis, Treatment and Follow\u2010Up","volume":"34","author":"Hendriks L. E.","year":"2023","journal-title":"Annals of Oncology"},{"issue":"2","key":"e_1_2_14_4_1","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nrclinonc.2017.166","article-title":"Tumour Heterogeneity and Resistance to cancer Therapies","volume":"15","author":"Dagogo\u2010Jack I.","year":"2018","journal-title":"Nature Reviews. Clinical Oncology"},{"issue":"2","key":"e_1_2_14_5_1","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1038\/s41591-025-04086-8","article-title":"Real\u2010World Clinical Utility of Comprehensive Genomic Profiling in Advanced Solid Tumors","volume":"32","author":"Saito Y.","year":"2026","journal-title":"Nature Medicine"},{"issue":"4","key":"e_1_2_14_6_1","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1111\/cas.13969","article-title":"Feasibility and Utility of a Panel Testing for 114 cancer\u2010Associated Genes in a Clinical Setting: A Hospital\u2010Based Study","volume":"110","author":"Sunami K.","year":"2019","journal-title":"Cancer Science"},{"issue":"5","key":"e_1_2_14_7_1","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1111\/cas.16130","article-title":"Nationwide Data From Comprehensive Genomic Profiling Assays for Detecting Driver Oncogenes in Non\u2010Small Cell Lung cancer","volume":"115","author":"Ishida M.","year":"2024","journal-title":"Cancer Science"},{"issue":"9","key":"e_1_2_14_8_1","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1093\/annonc\/mdy263","article-title":"A Framework to Rank Genomic Alterations as Targets for cancer Precision Medicine: The ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT)","volume":"29","author":"Mateo J.","year":"2018","journal-title":"Annals of Oncology"},{"issue":"8","key":"e_1_2_14_9_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0181968","article-title":"Versatile Ion S5XL Sequencer for Targeted Next Generation Sequencing of Solid Tumors in a Clinical Laboratory","volume":"12","author":"Mehrotra M.","year":"2017","journal-title":"PLoS One"},{"issue":"1","key":"e_1_2_14_10_1","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1111\/cas.15176","article-title":"Real\u2010World Data on NGS Using the Oncomine DxTT for Detecting Genetic Alterations in Non\u2010Small\u2010Cell Lung cancer: WJOG13019L","volume":"113","author":"Sakata S.","year":"2022","journal-title":"Cancer Science"},{"issue":"107190","key":"e_1_2_14_11_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.lungcan.2023.107190","article-title":"Clinical Application of the AMOY 9\u2010In\u20101 Panel to Lung cancer Patients","volume":"179","author":"Kunimasa K.","year":"2023","journal-title":"Lung Cancer"},{"issue":"8","key":"e_1_2_14_12_1","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.3390\/diagnostics13081476","article-title":"Analytical Performance of a Highly Sensitive System to Detect Gene Variants Using Next\u2010Generation Sequencing for Lung cancer Companion Diagnostics","volume":"13","author":"Kato K.","year":"2023","journal-title":"Diagnostics (Basel)"},{"issue":"11","key":"e_1_2_14_13_1","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1038\/nbt.2696","article-title":"Development and Validation of a Clinical cancer Genomic Profiling Test Based on Massively Parallel DNA Sequencing","volume":"31","author":"Frampton G. M.","year":"2013","journal-title":"Nature Biotechnology"},{"issue":"1","key":"e_1_2_14_14_1","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s13073-018-0547-0","article-title":"A Computational Tool to Detect DNA Alterations Tailored to Formalin\u2010Fixed Paraffin\u2010Embedded Samples in cancer Clinical Sequencing","volume":"10","author":"Kato M.","year":"2018","journal-title":"Genome Medicine"},{"issue":"4","key":"e_1_2_14_15_1","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1111\/cas.13968","article-title":"Comprehensive Assay for the Molecular Profiling of cancer by Target Enrichment From Formalin\u2010Fixed Paraffin\u2010Embedded Specimens","volume":"110","author":"Kohsaka S.","year":"2019","journal-title":"Cancer Science"},{"issue":"9","key":"e_1_2_14_16_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0237802","article-title":"Clinical and Analytical Validation of FoundationOne Liquid CDx, a Novel 324\u2010Gene cfDNA\u2010Based Comprehensive Genomic Profiling Assay for Cancers of Solid Tumor Origin","volume":"15","author":"Woodhouse R.","year":"2020","journal-title":"PLoS One"},{"issue":"15","key":"e_1_2_14_17_1","doi-asserted-by":"crossref","first-page":"3539","DOI":"10.1158\/1078-0432.CCR-17-3831","article-title":"Validation of a Plasma\u2010Based Comprehensive cancer Genotyping Assay Utilizing Orthogonal Tissue\u2010 and Plasma\u2010Based Methodologies","volume":"24","author":"Odegaard J. I.","year":"2018","journal-title":"Clinical Cancer Research"},{"issue":"12","key":"e_1_2_14_18_1","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1038\/s41591-020-1063-5","article-title":"Clinical Utility of Circulating Tumor DNA Sequencing in Advanced Gastrointestinal cancer: SCRUM\u2010Japan GI\u2010SCREEN and GOZILA Studies","volume":"26","author":"Nakamura Y.","year":"2020","journal-title":"Nature Medicine"},{"issue":"11","key":"e_1_2_14_19_1","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1158\/2159-8290.CD-22-0417","article-title":"C\u2010CAT: The National Datacenter for cancer Genomic Medicine in Japan","volume":"12","author":"Kohno T.","year":"2022","journal-title":"Cancer Discovery"},{"key":"e_1_2_14_20_1","unstructured":"R Core Team R: A Language and Environment for Statistical Computing R Foundation for Statistical Computing 2026."},{"issue":"9","key":"e_1_2_14_21_1","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1056\/NEJMoa2005653","article-title":"Efficacy of Selpercatinib in RET Fusion\u2010Positive Non\u2010Small\u2010Cell Lung cancer","volume":"383","author":"Drilon A.","year":"2020","journal-title":"New England Journal of Medicine"},{"issue":"7","key":"e_1_2_14_22_1","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1016\/S1470-2045(16)30146-2","article-title":"Dabrafenib Plus Trametinib in Patients With Previously Treated BRAF(V600E)\u2010Mutant Metastatic Non\u2010Small Cell Lung cancer: An Open\u2010Label, Multicentre Phase 2 Trial","volume":"17","author":"Planchard D.","year":"2016","journal-title":"Lancet Oncology"},{"issue":"1","key":"e_1_2_14_23_1","doi-asserted-by":"crossref","DOI":"10.1080\/14756366.2025.2481392","article-title":"Fourth\u2010Generation EGFR\u2010TKI to Overcome C797S Mutation: Past, Present, and Future","volume":"40","author":"Zhang D.","year":"2025","journal-title":"Journal of Enzyme Inhibition and Medicinal Chemistry"},{"key":"e_1_2_14_24_1","first-page":"OF1","article-title":"Telisotuzumab Adizutecan (ABBV\u2010400), a Novel c\u2010Met\u2010Targeting Antibody\u2010Drug Conjugate: First\u2010In\u2010Human Results in Advanced Gastric\/Gastroesophageal Junction cancer","volume":"30","author":"Strickler J. H.","year":"2026","journal-title":"Clinical Cancer Research"},{"issue":"9","key":"e_1_2_14_25_1","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/s41416-019-0573-8","article-title":"Resistance Mechanisms to Osimertinib in EGFR\u2010Mutated Non\u2010Small Cell Lung cancer","volume":"121","author":"Leonetti A.","year":"2019","journal-title":"British Journal of Cancer"},{"issue":"1","key":"e_1_2_14_26_1","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1038\/s41467-023-35962-x","article-title":"Analysis of Acquired Resistance Mechanisms to Osimertinib in Patients With EGFR\u2010Mutated Advanced Non\u2010Small Cell Lung cancer From the AURA3 Trial","volume":"14","author":"Chmielecki J.","year":"2023","journal-title":"Nature Communications"},{"issue":"8","key":"e_1_2_14_27_1","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1016\/S1470-2045(24)00270-5","article-title":"Tepotinib Plus Osimertinib in Patients With EGFR\u2010Mutated Non\u2010Small\u2010Cell Lung cancer With MET Amplification Following Progression on First\u2010Line Osimertinib (INSIGHT 2): A Multicentre, Open\u2010Label, Phase 2 Trial","volume":"25","author":"Wu Y.\u2010L.","year":"2024","journal-title":"Lancet Oncology"},{"issue":"3","key":"e_1_2_14_28_1","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/S1470-2045(19)30785-5","article-title":"Osimertinib Plus Savolitinib in Patients With EGFR Mutation\u2010Positive, MET\u2010Amplified, Non\u2010Small\u2010Cell Lung cancer After Progression on EGFR Tyrosine Kinase Inhibitors: Interim Results From a Multicentre, Open\u2010Label, Phase 1b Study","volume":"21","author":"Sequist L. V.","year":"2020","journal-title":"Lancet Oncology"}],"container-title":["Cancer Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.70538","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cas.70538","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.70538","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T12:22:10Z","timestamp":1790079730000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cas.70538"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,22]]},"references-count":27,"alternative-id":["10.1111\/cas.70538"],"URL":"https:\/\/doi.org\/10.1111\/cas.70538","archive":["Portico"],"relation":{},"ISSN":["1347-9032","1349-7006"],"issn-type":[{"value":"1347-9032","type":"print"},{"value":"1349-7006","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,22]]},"assertion":[{"value":"2026-07-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"cas.70538"}}