{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T09:04:55Z","timestamp":1784192695527,"version":"3.55.0"},"reference-count":109,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"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>Background\/Objectives: Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) has undergone rapid therapeutic evolution. However, heterogeneous outcomes persist, driven by mutations, central nervous system (CNS) involvement, and dynamic tumor burden reflected in part by circulating tumor DNA (ctDNA). As such, this review aims to summarize the most recent risk stratification frameworks in treating EGFR-mutant NSCLC, evaluate evidence supporting treatment intensification strategies and managing adverse effects, and explore the evolving role of ctDNA in guiding personalized therapy. Methods: A comprehensive literature search was conducted using major medical databases with a focus on key relevant studies on the workup and management of EGFR-mutant NSCLC. All authors reviewed the literature, assessed study quality, and interpreted the results from each study. Results: Molecular co-alterations, such as TP53 and RB1, as well as central nervous system (CNS) involvement, are consistently associated with inferior outcomes, supporting consideration of upfront treatment intensification. Combination strategies, including osimertinib plus chemotherapy or amivantamab-based regimens, demonstrate improved progression-free survival and delayed CNS progression when compared against osimertinib monotherapy. Intensification, however, is associated with a higher risk of increased toxicity, including dermatologic adverse events and infusion-related reactions. Finally, the utilization of circulating tumor DNA (ctDNA) has emerged as a strong prognostic marker, with ongoing trials investigating its predictive role for both escalation and de-escalation of therapy. Conclusions: The treatment paradigm for EGFR-mutant NSCLC is gradually evolving beyond first-line osimertinib to include a more integrated approach that considers molecular features, CNS involvement, and early ctDNA response. Although intensified regimens offer meaningful efficacy gains for high-risk patients, proactive toxicity management is essential to preserving quality of life. ctDNA-guided strategies represent a new and promising frontier for escalation and de-escalation of therapy, with results from ongoing trials poised to further refine personalized treatment algorithms.<\/jats:p>","DOI":"10.3390\/cancers18142285","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T08:08:34Z","timestamp":1784189314000},"page":"2285","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Risk Stratification and Strategies Towards Front-Line Therapy of EGFR-Mutant NSCLC: A Narrative Review"],"prefix":"10.3390","volume":"18","author":[{"given":"Kyle","family":"Taing","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Huntington Hospital, Pasadena, CA 91105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hei Yeung","family":"Lam","sequence":"additional","affiliation":[{"name":"Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3957-6106","authenticated-orcid":false,"given":"Robert","family":"Hsu","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Medicine, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1016\/j.annonc.2025.08.003","article-title":"Early and Locally Advanced Non-Small-Cell Lung Cancer: ESMO Clinical Practice Guideline for Diagnosis, Treatment and Follow-Up","volume":"36","author":"Zer","year":"2025","journal-title":"Ann. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/j.jtho.2024.03.016","article-title":"Unveiling the Landscape of Uncommon EGFR Mutations in NSCLC\u2014A Systematic Review","volume":"19","author":"Borgeaud","year":"2024","journal-title":"J. Thorac. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/S2213-2600(24)00428-4","article-title":"Estimated Worldwide Variation and Trends in Incidence of Lung Cancer by Histological Subtype in 2022 and Over Time: A Population-Based Study","volume":"13","author":"Luo","year":"2025","journal-title":"Lancet Respir. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s40291-021-00563-1","article-title":"Worldwide Prevalence of Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancer: A Meta-Analysis","volume":"26","author":"Melosky","year":"2022","journal-title":"Mol. Diagn. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1056\/NEJMoa0810699","article-title":"Gefitinib or Carboplatin\u2013Paclitaxel in Pulmonary Adenocarcinoma","volume":"361","author":"Mok","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S1470-2045(11)70393-X","article-title":"Erlotinib Versus Standard Chemotherapy as First-Line Treatment for European Patients with Advanced EGFR Mutation-Positive Non-Small-Cell Lung Cancer (EURTAC): A Multicentre, Open-Label, Randomised Phase 3 Trial","volume":"13","author":"Rosell","year":"2012","journal-title":"Lancet Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3327","DOI":"10.1200\/JCO.2012.44.2806","article-title":"Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients with Metastatic Lung Adenocarcinoma with EGFR Mutations","volume":"31","author":"Sequist","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1056\/NEJMoa2027071","article-title":"Osimertinib in Resected EGFR-Mutated Non\u2013Small-Cell Lung Cancer","volume":"383","author":"Wu","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1056\/NEJMoa2402614","article-title":"Osimertinib after Chemoradiotherapy in Stage III EGFR -Mutated NSCLC","volume":"391","author":"Lu","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2875","DOI":"10.1200\/JCO-25-00883","article-title":"Neoadjuvant Osimertinib for Resectable EGFR -Mutated Non\u2013Small Cell Lung Cancer","volume":"43","author":"He","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1056\/NEJMoa044238","article-title":"EGFR Mutation and Resistance of Non-Small-Cell Lung Cancer to Gefitinib","volume":"352","author":"Kobayashi","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2070","DOI":"10.1073\/pnas.0709662105","article-title":"The T790M Mutation in EGFR Kinase Causes Drug Resistance by Increasing the Affinity for ATP","volume":"105","author":"Yun","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"i10","DOI":"10.1093\/annonc\/mdx703","article-title":"Mechanisms of Acquired Resistance to First- and Second-Generation EGFR Tyrosine Kinase Inhibitors","volume":"29","author":"Westover","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1158\/2159-8290.CD-14-0337","article-title":"AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer","volume":"4","author":"Cross","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1056\/NEJMoa1612674","article-title":"Osimertinib or Platinum\u2013Pemetrexed in EGFR T790M\u2013Positive Lung Cancer","volume":"376","author":"Mok","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1056\/NEJMoa1913662","article-title":"Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC","volume":"382","author":"Ramalingam","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/s43018-021-00195-8","article-title":"Overcoming Therapy Resistance in EGFR-Mutant Lung Cancer","volume":"2","author":"Passaro","year":"2021","journal-title":"Nat. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/s41416-019-0573-8","article-title":"Resistance Mechanisms to Osimertinib in EGFR-Mutated Non-Small Cell Lung Cancer","volume":"121","author":"Leonetti","year":"2019","journal-title":"Br. J. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.jtho.2023.11.016","article-title":"Allelic Context of EGFR C797X-Mutant Lung Cancer Defines Four Subtypes With Heterogeneous Genomic Landscape and Distinct Clinical Outcomes","volume":"19","author":"Lu","year":"2024","journal-title":"J. Thorac. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1056\/NEJMoa2306434","article-title":"Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC","volume":"389","author":"Planchard","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1056\/NEJMoa2510308","article-title":"FLAURA2 Investigators Survival with Osimertinib plus Chemotherapy in EGFR-Mutated Advanced NSCLC","volume":"394","author":"Planchard","year":"2026","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1056\/NEJMoa2403614","article-title":"Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC","volume":"391","author":"Cho","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1056\/NEJMoa2503001","article-title":"Overall Survival with Amivantamab-Lazertinib in EGFR-Mutated Advanced NSCLC","volume":"393","author":"Yang","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1016\/j.jtho.2025.06.030","article-title":"Lazertinib Versus Osimertinib in Previously Untreated EGFR-Mutant Advanced NSCLC: A Randomized, Double-Blind, Exploratory Analysis From MARIPOSA","volume":"20","author":"Lee","year":"2025","journal-title":"J. Thorac. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"105807","DOI":"10.1016\/j.esmoop.2025.105807","article-title":"COMPEL: Osimertinib plus platinum-based chemotherapy in patients with EGFR-mutated advanced NSCLC and progression on first-line osimertinib","volume":"10","author":"Peled","year":"2025","journal-title":"ESMO Open."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"384","DOI":"10.3892\/ol.2022.13504","article-title":"Concurrent TP53 mutations predict a poor prognosis of EGFR-mutant NSCLCs treated with TKIs: An updated systematic review and meta-analysis","volume":"24","author":"Lan","year":"2022","journal-title":"Oncol. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Kobayashi, K. (2026). TP53 Functional-Domain-Specific Mutations Define Distinct Clinical Outcomes in EGFR-Mutant Non-Small Cell Lung Cancer Treated with EGFR Tyrosine Kinase Inhibitors. J. Clin. Med., 15.","DOI":"10.3390\/jcm15041552"},{"key":"ref_28","first-page":"3159","article-title":"Mutations in exon 8 of TP53 are associated with shorter survival in patients with advanced lung cancer","volume":"18","author":"Liu","year":"2019","journal-title":"Oncol. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1038\/s41418-022-00989-y","article-title":"Mutant p53: It\u2019s not all one and the same","volume":"29","author":"Kennedy","year":"2022","journal-title":"Cell Death Differ."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/s41698-024-00557-2","article-title":"TP53 gain-of-function mutations promote osimertinib resistance via TNF-\u03b1\u2013NF-\u03baB signaling in EGFR-mutated lung cancer","volume":"8","author":"Ibusuki","year":"2024","journal-title":"npj Precis. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"108018","DOI":"10.1016\/j.esmoop.2026.108018","article-title":"Association of TP53 gain-of-function mutations with early osimertinib resistance in epidermal growth factor receptor-mutant lung adenocarcinoma","volume":"11","author":"Ibusuki","year":"2026","journal-title":"ESMO Open"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/j.jtho.2022.02.011","article-title":"Concurrent TP53 Mutations Facilitate Resistance Evolution in EGFR-Mutant Lung Adenocarcinoma","volume":"17","author":"Vokes","year":"2022","journal-title":"J. Thorac. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5959721","DOI":"10.1155\/2016\/5959721","article-title":"Roles of pRB in the Regulation of Nucleosome and Chromatin Structures","volume":"2016","author":"Uchida","year":"2016","journal-title":"BioMed Res. Int."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6377","DOI":"10.1038\/ncomms7377","article-title":"RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer","volume":"6","author":"Niederst","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1016\/j.jtho.2019.06.002","article-title":"Concurrent RB1 and TP53 Alterations Define a Subset of EGFR-Mutant Lung Cancers at risk for Histologic Transformation and Inferior Clinical Outcomes","volume":"14","author":"Offin","year":"2019","journal-title":"J. Thorac. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"8565","DOI":"10.1200\/JCO.2024.42.16_suppl.8565","article-title":"Osimertinib, platinum, etoposide as initial treatment for patients with EGFR mutant lung cancers with TP53 and RB1 alterations","volume":"42","author":"Chen","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Sun, H., Ren, P., Chen, Y., Lan, L., Yan, Z., Yang, Y., Wang, B., Wang, C., Li, Y., and Li, L. (2023). Optimal therapy for concomitant EGFR and TP53 mutated non-small cell lung cancer: A real-world study. BMC Cancer, 23.","DOI":"10.1186\/s12885-023-10637-4"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Shang, K., Huang, H., Xu, Y., Guo, Y., Chen, Y., Zhu, Y., Ren, F., and Cao, J. (2022). Efficacy and Safety Analyses of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Combined With Chemotherapy in the Treatment of Advanced Non-Small-Cell Lung Cancer With an EGFR\/TP53 Co-Mutation. BMC Cancer, 22.","DOI":"10.1186\/s12885-022-10391-z"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.annonc.2024.05.541","article-title":"Amivantamab Plus Lazertinib Versus Osimertinib in First-Line EGFR-Mutant Advanced Non-Small-Cell Lung Cancer With Biomarkers of High-Risk Disease: A Secondary Analysis From MARIPOSA","volume":"35","author":"Felip","year":"2024","journal-title":"Ann. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"106309","DOI":"10.1016\/j.esmoop.2026.106309","article-title":"2O Osimertinib (osi) with or without chemotherapy (CTx) as first-line treatment in EGFR-mutant (EGFRm) advanced NSCLC with concurrent TP53 mutations (TOP study)","volume":"11","author":"Yang","year":"2026","journal-title":"ESMO Open"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Deng, F., Ma, W., and Wei, S. (2026). Targeting mesenchymal-epidermal transition (MET) aberrations in non-small cell lung cancer: Current challenges and therapeutic advances. Cancers, 18.","DOI":"10.3390\/cancers18020207"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S0140-6736(25)01811-2","article-title":"Savolitinib plus osimertinib versus chemotherapy for advanced, EGFR mutation-positive, MET-amplified non-small-cell lung cancer in China (SACHI): Interim analysis of a multicentre, open-label, phase 3 randomised controlled trial","volume":"407","author":"Lu","year":"2026","journal-title":"Lancet"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1016\/S1470-2045(24)00270-5","article-title":"Tepotinib plus osimertinib in patients with EGFR-mutated non-small-cell lung cancer with MET amplification following progression on first-line osimertinib (INSIGHT 2): A multicentre, open-label, phase 2 trial","volume":"25","author":"Wu","year":"2024","journal-title":"Lancet Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Wang, L., Hu, H., Pan, Y., Wang, R., Li, Y., Shen, L., Yu, Y., Li, H., Cai, D., and Sun, Y. (2014). PIK3CA Mutations Frequently Coexist With EGFR\/KRAS Mutations in Non-Small Cell Lung Cancer and Suggest Poor Prognosis in EGFR\/KRAS Wildtype Subgroup. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0088291"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"108747","DOI":"10.1016\/j.lungcan.2025.108747","article-title":"Clinical factors and molecular co-alterations impact outcomes in patients receiving first-line osimertinib for EGFR-mutated non-small cell lung cancer","volume":"2028","author":"Sun","year":"2025","journal-title":"Lung Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.cllc.2020.12.008","article-title":"PTEN Loss as a Predictor of Tumor Heterogeneity and Poor Prognosis in Patients with EGFR-Mutant Advanced Non-Small-Cell Lung Cancer Receiving Tyrosine Kinase Inhibitors","volume":"22","author":"Ferrara","year":"2021","journal-title":"Clin. Lung Cancer"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.jtho.2018.10.150","article-title":"Concurrent Genetic Alterations Predict the Progression to Target Therapy in EGFR-Mutated Advanced NSCLC","volume":"14","author":"Kim","year":"2019","journal-title":"J. Thorac. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3256","DOI":"10.1158\/0008-5472.CAN-08-4055","article-title":"PTEN Loss Contributes to Erlotinib Resistance in EGFR-Mutant Lung Cancer by Activation of Akt and EGFR","volume":"69","author":"Sos","year":"2009","journal-title":"Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Chang, W.J., Sung, J.S., Lee, S.Y., Kang, E.J., Kwon, N.J., Kim, H.M., Shin, S.W., Choi, J.Y., Choi, Y.J., and Kim, J.W. (2020). The Clinical Significance of RAS, PIK3CA, and PTEN Mutations in Non-Small Cell Lung Cancer Using Cell-Free DNA. J. Clin. Med., 9.","DOI":"10.3390\/jcm9082642"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2309","DOI":"10.1038\/onc.2016.385","article-title":"In vivo oncogenic conflict triggered by co-existing KRAS and EGFR activating mutations in lung adenocarcinoma","volume":"36","author":"Ambrogio","year":"2016","journal-title":"Oncogene"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1001\/jamaoncol.2016.0405","article-title":"Prognostic and Predictive Value in KRAS in Non\u2013Small-Cell Lung Cancer: A Review","volume":"2","author":"Wood","year":"2016","journal-title":"JAMA Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e2300520","DOI":"10.1200\/PO.23.00520","article-title":"Landscape of Concomitant Driver Alterations in Classical EGFR-Mutated Non\u2013Small Cell Lung Cancer","volume":"8","author":"Wang","year":"2024","journal-title":"JCO Precis. Oncol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e21201","DOI":"10.1200\/JCO.2023.41.16_suppl.e21201","article-title":"Liquid and tissue profiling of targetable co-mutations with KRAS in non-small cell lung cancer","volume":"41","author":"Rohatgi","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e2500231","DOI":"10.1200\/GO-25-00231","article-title":"Prevalence of Genomic Alterations in EGFR, KRAS, NRAS, and BRAF Among Early-Stage Nonsquamous Non-Small Cell Lung Cancer in Brazil","volume":"12","author":"Marques","year":"2026","journal-title":"JCO Glob. Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"8634","DOI":"10.1200\/JCO.2026.44.16_suppl.8634","article-title":"Clinicogenomic determinants of early progression on first-line osimertinib in EGFR-mutant NSCLC","volume":"44","author":"Pecci","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Slomka, J., Berthou, H., Mansuet-Lupo, A., Blons, H., Fabre, E., Lerner, I., Rance, B., Alifano, M., Chapron, J., and Birsen, G. (2024). Clinical and Molecular Characteristics Associated With High PD-L1 Expression in EGFR-Mutated Lung Adenocarcinoma. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0307161"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1016\/j.jtho.2023.06.017","article-title":"Genomic Alterations and the Incidence of Brain Metastases in Advanced and Metastatic NSCLC: A Systematic Review and Meta-Analysis","volume":"18","author":"Gillespie","year":"2023","journal-title":"J. Thorac. Oncol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1962","DOI":"10.1016\/j.jtho.2016.06.029","article-title":"Leptomeningeal Metastases in Patients with NSCLC with EGFR Mutations","volume":"11","author":"Li","year":"2016","journal-title":"J. Thorac. Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Remon, J., and Besse, B. (2018). Brain Metastases in Oncogene-Addicted Non-Small Cell Lung Cancer Patients: Incidence and Treatment. Front. Oncol., 8.","DOI":"10.3389\/fonc.2018.00088"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1158\/1078-0432.CCR-11-2529","article-title":"Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in the Treatment of Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer Metastatic to the Brain","volume":"18","author":"Spicer","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"S80","DOI":"10.21037\/atm.2019.04.04","article-title":"Brain Metastases in EGFR-Positive Non-Small Cell Lung Cancer: The Way to the Sanctuary Becomes Less Winding","volume":"7","author":"Passaro","year":"2019","journal-title":"Ann. Transl. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1056\/NEJMoa1713137","article-title":"Osimertinib in Untreated EGFR-Mutated Advanced Non\u2013Small-Cell Lung Cancer","volume":"378","author":"Soria","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3290","DOI":"10.1200\/JCO.2018.78.3118","article-title":"CNS Response to Osimertinib Versus Standard Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With Untreated EGFR-Mutated Advanced Non\u2013Small-Cell Lung Cancer","volume":"36","author":"Reungwetwattana","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1016\/j.annonc.2020.06.017","article-title":"A Phase II, Multicenter, Two Cohort Study of 160 mg Osimertinib in EGFR T790M-Positive Non-Small-Cell Lung Cancer Patients With Brain Metastases or Leptomeningeal Disease Who Progressed on Prior EGFR TKI Therapy","volume":"31","author":"Park","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1200\/JCO.19.00457","article-title":"Osimertinib in Patients With Epidermal Growth Factor Receptor Mutation\u2013Positive Non\u2013Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study","volume":"38","author":"Yang","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1001\/jamaoncol.2025.1779","article-title":"High-Dose Aumolertinib for Untreated EGFR-Variant Non\u2013Small Cell Lung Cancer With Brain Metastases: The ACHIEVE Phase 2 Nonrandomized Clinical Trial","volume":"11","author":"Li","year":"2025","journal-title":"JAMA Oncol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e15","DOI":"10.1200\/JCO-25-02822","article-title":"Therapy for Stage IV Non\u2013Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, 2026.3.0","volume":"44","author":"Puri","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1200\/JCO.23.02219","article-title":"CNS Efficacy of Osimertinib With or Without Chemotherapy in Epidermal Growth Factor Receptor-Mutated Advanced Non-Small-Cell Lung Cancer","volume":"42","author":"Planchard","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"22901","DOI":"10.1038\/s41598-024-74496-0","article-title":"First-Line Treatment of EGFR-Mutated Non-Small Cell Lung Cancer With Brain Metastases: A Systematic Review and Meta-Analysis","volume":"14","author":"Ma","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"102807","DOI":"10.1016\/j.ctrv.2024.102807","article-title":"Central nervous system metastases in advanced non-small cell lung cancer: A review of the therapeutic landscape","volume":"130","author":"Weller","year":"2024","journal-title":"Cancer Treat. Rev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"103505","DOI":"10.1016\/j.jtho.2025.10.012","article-title":"Phase 2 Study of Amivantamab Plus Lazertinib in Previously Treated Patients With EGFR-Mutant Lung Cancers With Brain and Leptomeningeal Metastases","volume":"21","author":"Chen","year":"2026","journal-title":"J. Thorac. Oncol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/j.annonc.2025.04.003","article-title":"Savolitinib plus osimertinib in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer with MET overexpression and\/or amplification following disease progression on osimertinib: Primary results from the phase II SAVANNAH study","volume":"36","author":"Kim","year":"2025","journal-title":"Ann. Oncol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1200\/JCO-24-01349","article-title":"Datopotamab Deruxtecan in Advanced or Metastatic Non-Small Cell Lung Cancer With Actionable Genomic Alterations: Results From the Phase II TROPION-Lung05 Study","volume":"43","author":"Sands","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1016\/j.annonc.2026.02.014","article-title":"Osimertinib plus datopotamab deruxtecan in patients with EGFR-mutated advanced NSCLC after progression on first-line osimertinib: ORCHARD","volume":"37","author":"Riess","year":"2026","journal-title":"Ann. Oncol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1200\/JCO.2025.43.16_suppl.TPS8647","article-title":"TROPION-Lung14: A phase 3 study of osimertinib \u00b1 datopotamab deruxtecan (Dato-DXd) as first-line (1L) treatment for patients with EGFR -mutated locally advanced or metastatic (LA\/M) non-small cell lung cancer (NSCLC)","volume":"43","author":"Lu","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"HARMONi-A Study Investigators, Fang, W., Zhao, Y., Luo, Y., Yang, R., Huang, Y., He, Z., Zhao, H., Li, M., and Li, K. (2024). Ivonescimab Plus Chemotherapy in Non-Small Cell Lung Cancer With EGFR Variant: A Randomized Clinical Trial. JAMA, 332, 561\u2013570. Erratum in JAMA\u00a02026, 335, 554. https:\/\/doi.org\/10.1001\/jama.2025.27164.","DOI":"10.1001\/jama.2025.27164"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3110","DOI":"10.1200\/JCO.2025.43.16_suppl.3110","article-title":"Anti-tumor activity of BH-30643, a novel macrocyclic kinase inhibitor, in EGFR -mutant lung cancer models","volume":"43","author":"Deng","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e2500977","DOI":"10.1200\/PO-25-00977","article-title":"Potential of Minimal Residual Disease in Guiding Adjuvant Therapy Decisions in Non-Small Cell Lung Cancer","volume":"10","author":"Lei","year":"2026","journal-title":"JCO Precis. Oncol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1016\/j.annonc.2025.06.001","article-title":"Identifying the genomic landscape of EGFR-mutant lung cancers with central nervous system metastases","volume":"36","author":"Wilcox","year":"2025","journal-title":"Ann. Oncol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e209077","DOI":"10.1001\/jamanetworkopen.2020.9077","article-title":"Association of Cerebrospinal Fluid Tumor DNA Genotyping With Survival Among Patients With Lung Adenocarcinoma and Central Nervous System Metastases","volume":"3","author":"Li","year":"2020","journal-title":"JAMA Netw. Open"},{"key":"ref_81","first-page":"545","article-title":"Homocysteine and Methylmalonic Acid: Markers to Predict and Avoid Toxicity From Pemetrexed Therapy","volume":"1","author":"Niyikiza","year":"2002","journal-title":"Mol. Cancer Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1016\/j.jtho.2025.07.117","article-title":"Enhanced Versus Standard Dermatologic Management With Amivantamab-Lazertinib in EGFR-Mutated Advanced NSCLC: The COCOON Global Randomized Controlled Trial","volume":"20","author":"Cho","year":"2025","journal-title":"J. Thorac. Oncol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.jtho.2025.01.018","article-title":"Preventing Infusion-Related Reactions With Intravenous Amivantamab-Results From SKIPPirr, a Phase 2 Study: A Brief Report","volume":"20","author":"Spira","year":"2025","journal-title":"J. Thorac. Oncol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"3593","DOI":"10.1200\/JCO.24.01001","article-title":"PALOMA-3 Investigators. Subcutaneous Versus Intravenous Amivantamab, Both in Combination With Lazertinib, in Refractory Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer: Primary Results From the Phase III PALOMA-3 Study","volume":"42","author":"Leighl","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Dai, Y., Xiao, C., Chen, Q., Wang, L., Bo, R., Cheng, Z., and Pan, G. (2026). Efficacy and safety of ivonescimab in non-small cell lung cancer: A systematic review and meta-analysis of emerging clinical data. Front. Pharmacol., 17.","DOI":"10.3389\/fphar.2026.1770637"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1038\/nm.1789","article-title":"Circulating Mutant DNA to Assess Tumor Dynamics","volume":"14","author":"Diehl","year":"2008","journal-title":"Nat. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1158\/1055-9965.EPI-15-0893","article-title":"Circulating DNA and Survival in Solid Tumors","volume":"25","author":"Templeton","year":"2016","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1111\/1759-7714.12793","article-title":"Correlation Between Progression-Free Survival, Tumor Burden, and Circulating Tumor DNA in the Initial Diagnosis of Advanced-Stage EGFR-Mutated Non-Small Cell Lung Cancer","volume":"9","author":"Lee","year":"2018","journal-title":"Thorac. Cancer"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"102228","DOI":"10.1016\/j.tranon.2024.102228","article-title":"Clinical Characteristics of EGFR-ctDNA Shedders in EGFR-Mutant NSCLC Patients","volume":"52","author":"Ruglioni","year":"2025","journal-title":"Transl. Oncol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"3340","DOI":"10.1158\/1078-0432.CCR-22-3146","article-title":"Early Clearance of Plasma Epidermal Growth Factor Receptor Mutations as a Predictor of Outcome on Osimertinib in Advanced Non-Small Cell Lung Cancer; Exploratory Analysis from AURA3 and FLAURA","volume":"29","author":"Gray","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"CT017","DOI":"10.1158\/1538-7445.AM2024-CT017","article-title":"Abstract CT017: FLAURA2: Exploratory analysis of baseline (BL) and on-treatment plasma EGFRm dynamics in patients (pts) with EGFRm advanced NSCLC treated with first-line (1L) osimertinib (osi) \u00b1 platinum-pemetrexed","volume":"84","author":"Kobayashi","year":"2024","journal-title":"Cancer Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1016\/j.jtho.2024.07.008","article-title":"Longitudinal Analyses of Circulating Tumor DNA for the Detection of EGFR Mutation-Positive Advanced NSCLC Progression During Treatment: Data From FLAURA and AURA3","volume":"19","author":"Gray","year":"2024","journal-title":"J. Thorac. Oncol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1001\/jamaoncol.2024.1779","article-title":"Circulating Tumor DNA-Guided De-Escalation Targeted Therapy for Advanced Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial","volume":"10","author":"Dong","year":"2024","journal-title":"JAMA Oncol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.annonc.2023.02.012","article-title":"Osimertinib treatment based on plasma T790M monitoring in patients with EGFR-mutant non-small-cell lung cancer (NSCLC): EORTC Lung Cancer Group 1613 APPLE phase II randomized clinical trial","volume":"34","author":"Remon","year":"2023","journal-title":"Ann. Oncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.21037\/tlcr-24-185","article-title":"The APPLE Trial in the Evolving Landscape of ctDNA Monitoring","volume":"13","author":"Brazel","year":"2024","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"e473","DOI":"10.1016\/j.cllc.2022.07.019","article-title":"Study Design and Rationale for the PACE-LUNG Trial: A Multicenter, Single-Arm, Phase II Clinical Trial Evaluating the Efficacy of Additional Chemotherapy for Patients with EGFRm NSCLC with the Continued Presence of Plasma ctDNA EGFRm at Week 3 After Start of Osimertinib First-Line Treatment","volume":"23","author":"Acker","year":"2022","journal-title":"Clin. Lung Cancer"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.lungcan.2018.07.003","article-title":"The prognostic value of TP53 and its correlation with EGFR mutation in advanced non-small cell lung cancer, an analysis based on cBioPortal data base","volume":"123","author":"Jiao","year":"2018","journal-title":"Lung Cancer"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Kuang, L., Zhang, Y., Wang, H., Wang, P., and Li, Y. (2025). Prognostic Factors Influencing Overall Survival in Stage IV EGFR-Mutant NSCLC Patients Treated With EGFR-TKIs. BMC Pulm. Med., 25.","DOI":"10.1186\/s12890-025-03569-1"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"e20594","DOI":"10.1200\/JCO.2024.42.16_suppl.e20594","article-title":"Prognostic factors and long-term survivors in EGFR-mutated lung cancer: A multi-institutional retrospective analysis","volume":"42","author":"Kuan","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"8839","DOI":"10.1038\/ncomms9839","article-title":"Cerebrospinal Fluid-Derived Circulating Tumour DNA Better Represents the Genomic Alterations of Brain Tumours Than Plasma","volume":"6","author":"Mayor","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_101","unstructured":"Lu, S. (2026, July 13). A Study of Osimertinib-Based Adaptive Treatment Guided by ctDNA EGFRm+ Monitoring in NSCLC. ClinicalTrials.gov 2024, NCT07058519, Available online: https:\/\/clinicaltrials.gov\/study\/NCT07058519."},{"key":"ref_102","unstructured":"Zhou, Q., and Zhang, Y.C. (2026, July 13). A ctDNA-Guided Phase II Trial of Osimertinib in Combination with Sacituzumab Tirumotecan in EGFR-Mutated Advanced NSCLC Patients with Positive ctDNA After Lead-In Osimertinib Monotherapy. ClinicalTrials.gov 2025, NCT07375316, Available online: https:\/\/clinicaltrials.gov\/study\/NCT07375316."},{"key":"ref_103","first-page":"233","article-title":"Integrating ctDNA testing for EGFR analysis in advanced non-small cell lung cancer: Strategies for clinical laboratories","volume":"6","year":"2025","journal-title":"Adv. Lab. Med.\/Av. Med. Lab."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"3752","DOI":"10.1158\/1078-0432.CCR-22-0741","article-title":"Circulating Tumor DNA Kinetics Predict Progression-Free and Overall Survival in EGFR TKI\u2013Treated Patients with EGFR -Mutant NSCLC (SWOG S1403)","volume":"28","author":"Mack","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Cho, M.S., Park, C.H., Lee, S., and Park, H.S. (2020). Clinicopathological parameters for circulating tumor DNA shedding in surgically resected non-small cell lung cancer with EGFR or KRAS mutation. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0230622"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Thalambedu, N., Balla, M., Sivasubramanian, B.P., Sadaram, P., Malla, K.P., Vasipalli, K.P., and Kakadia, S. (2025). Integrating artificial intelligence with circulating tumor DNA for non-small cell lung cancer: Opportunities, challenges, and future directions. Front. Med., 12.","DOI":"10.3389\/fmed.2025.1612376"},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Khan, S., Upadhyay, S., Kauser, S., Hasan, G.M., Lu, W., Waters, M., Hassan, M.I., and Sohal, S.S. (2025). Redefining the Diagnostic and Therapeutic Landscape of Non-Small Cell Lung Cancer in the Era of Precision Medicine. J. Clin. Med., 14.","DOI":"10.3390\/jcm14228021"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e71578","DOI":"10.1002\/cam4.71578","article-title":"Digital Biomarkers for Precision Early Detection of Lung Cancer: Integrating AI-Driven Multi-Omics Into Clinical Pathways","volume":"15","author":"Bu","year":"2026","journal-title":"Cancer Med."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"8139","DOI":"10.2147\/IJN.S477851","article-title":"Unraveling the Connection: Extracellular Vesicles and Non-Small Cell Lung Cancer","volume":"19","author":"Wu","year":"2024","journal-title":"Int. J. Nanomed."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/14\/2285\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T08:28:06Z","timestamp":1784190486000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/14\/2285"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,16]]},"references-count":109,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cancers18142285"],"URL":"https:\/\/doi.org\/10.3390\/cancers18142285","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,16]]}}}