{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:48:35Z","timestamp":1787028515073,"version":"build-2736575974"},"reference-count":126,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T00:00:00Z","timestamp":1684281600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The majority of epidermal growth factor receptor (EGFR) mutations (85\u201390%) are exon 19 deletions and L858R point mutations of exon 21, characterized by high sensitivity to EGFR-tyrosine kinase inhibitors (TKIs). Less is known about uncommon mutations (10\u201315% of EGFR mutations). The predominant mutation types in this category include exon 18 point mutations, exon 21 L861X, exon 20 insertions, and exon 20 S768I. This group shows a heterogeneous prevalence, partly due to different testing methods and to the presence of compound mutations, which in some cases can lead to shorter overall survival and different sensitivity to different TKIs compared to simple mutations. Additionally, EGFR-TKI sensitivity may also vary depending on the specific mutation and the tertiary structure of the protein. The best strategy remains uncertain, and the data of EGFR-TKIs efficacy are based on few prospective and some retrospective series. Newer investigational agents are still under study, and there are no other approved specific treatments targeting uncommon EGFR mutations. Defining the best treatment option for this patient population remains an unmet medical need. The objective of this review is to evaluate existing data on the outcomes, epidemiology, and clinical characteristics of lung cancer patients with rare EGFR mutations, with a focus on intracranial activity and response to immunotherapy.<\/jats:p>","DOI":"10.3390\/ijms24108878","type":"journal-article","created":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T02:04:05Z","timestamp":1684289045000},"page":"8878","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Overview on Therapeutic Options in Uncommon EGFR Mutant Non-Small Cell Lung Cancer (NSCLC): New Lights for an Unmet Medical Need"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5550-1211","authenticated-orcid":false,"given":"Giulia","family":"Pretelli","sequence":"first","affiliation":[{"name":"Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Calogera Claudia","family":"Spagnolo","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, Department of Human Pathology \u201cG. Barresi\u201d, University of Messina, 98122 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0813-3126","authenticated-orcid":false,"given":"Giuliana","family":"Ciappina","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, Department of Human Pathology \u201cG. Barresi\u201d, University of Messina, 98122 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariacarmela","family":"Santarpia","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, Department of Human Pathology \u201cG. Barresi\u201d, University of Messina, 98122 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Pasello","sequence":"additional","affiliation":[{"name":"Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy"},{"name":"Oncologia Medica 2, Istituto Oncologico Veneto, IRCCS, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/s41392-019-0099-9","article-title":"The emerging treatment landscape of targeted therapy in non-small-cell lung cancer","volume":"4","author":"Yuan","year":"2019","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1056\/NEJMra0707704","article-title":"EGFR antagonists in cancer treatment","volume":"358","author":"Ciardiello","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/nrclinonc.2009.62","article-title":"Somatic EGFR mutations and efficacy of tyrosine kinase inhibitors in NSCLC","volume":"6","author":"Linardou","year":"2009","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"78985","DOI":"10.18632\/oncotarget.12587","article-title":"The prevalence of EGFR mutation in patients with non-small cell lung cancer: A systematic review and meta-analysis","volume":"7","author":"Zhang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1097\/JTO.0b013e3182781e35","article-title":"Compound EGFR mutations and response to EGFR tyrosine kinase inhibitors","volume":"8","author":"Kobayashi","year":"2013","journal-title":"J. Thorac. Oncol."},{"key":"ref_7","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_8","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_9","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1007\/s12253-018-0460-2","article-title":"Large-scale EGFR mutation testing in clinical practice: Analysis of a series of 18,920 non-small cell lung cancer cases","volume":"25","author":"Evans","year":"2019","journal-title":"Pathol. Oncol. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"102080","DOI":"10.1016\/j.canep.2021.102080","article-title":"Uncommon EGFR mutations in non-small-cell lung cancer: A systematic literature review of prevalence and clinical outcomes","volume":"76","author":"John","year":"2022","journal-title":"Cancer Epidemiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"8575","DOI":"10.2147\/OTT.S160358","article-title":"Afatinib versus gemcitabine\/cisplatin for first-line treatment of Chinese patients with advanced non-small-cell lung cancer harboring EGFR mutations: Subgroup analysis of the LUX-Lung 6 trial","volume":"11","author":"Wu","year":"2018","journal-title":"OncoTargets Ther."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ho, G.-F., Chai, C.-S., Alip, A., Wahid, M.I.A., Abdullah, M.M., Foo, Y.-C., How, S.-H., Zaatar, A., Lam, K.-S., and Leong, K.-W. (2019). Real-world experience of first-line afatinib in patients with EGFR-mutant advanced NSCLC: A multicenter observational study. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-6107-1"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1007\/s10147-021-01869-0","article-title":"Experience from Asian centers in a named-patient-use program for afatinib in patients with advanced non-small-cell lung cancer who had progressed following prior therapies, including patients with uncommon EGFR mutations","volume":"26","author":"Chang","year":"2021","journal-title":"Int. J. Clin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1016\/S1470-2045(15)00026-1","article-title":"Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: A combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6","volume":"16","author":"Yang","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/j.jtho.2020.12.002","article-title":"Recent advances on the role of EGFR tyrosine kinase inhibitors in the management of NSCLC With uncommon, non exon 20 insertions, EGFR mutations","volume":"16","author":"Passaro","year":"2021","journal-title":"J. Thorac. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"709877","DOI":"10.3389\/fonc.2021.709877","article-title":"Afatinib in EGFR TKI-naive patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer: A pooled analysis of three phase IIIb studies","volume":"11","author":"Passaro","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1093\/oncolo\/oyac022","article-title":"Tyrosine kinase inhibitor activity in patients with NSCLC harboring uncommon EGFR mutations: A Retrospective international cohort study (UpSwinG)","volume":"27","author":"Popat","year":"2022","journal-title":"Oncologist"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.lungcan.2017.11.005","article-title":"A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer","volume":"114","author":"Tu","year":"2017","journal-title":"Lung Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Russo, A., Franchina, T., Ricciardi, G., Battaglia, A., Picciotto, M., and Adamo, V. (2019). Heterogeneous responses to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with uncommon EGFR mutations: New insights and future perspectives in this complex clinical scenario. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20061431"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"101994","DOI":"10.1016\/j.ctrv.2020.101994","article-title":"The significance of epidermal growth factor receptor uncommon mutations in non-small cell lung cancer: A systematic review and critical appraisal","volume":"85","author":"Gristina","year":"2020","journal-title":"Cancer Treat. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"100398","DOI":"10.1016\/j.ctarc.2021.100398","article-title":"Rare epidermal growth factor receptor gene alterations in non-small cell lung cancer patients, tyrosine kinase inhibitor response and outcome analysis","volume":"28","author":"Mehta","year":"2021","journal-title":"Cancer Treat. Res. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"163","DOI":"10.5858\/arpa.2016-0579-CP","article-title":"Worldwide frequency of commonly detected EGFR mutations","volume":"142","author":"Graham","year":"2018","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"103300","DOI":"10.1016\/j.critrevonc.2021.103300","article-title":"Dealing with NSCLC EGFR mutation testing and treatment: A comprehensive review with an Italian real-world perspective","volume":"160","author":"Malapelle","year":"2021","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/s41586-021-03898-1","article-title":"Structure-based classification predicts drug response in EGFR-mutant NSCLC","volume":"597","author":"Robichaux","year":"2021","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.lungcan.2019.10.030","article-title":"Detection of rare and novel EGFR mutations in NSCLC patients: Implications for treatment-decision","volume":"139","author":"Sousa","year":"2020","journal-title":"Lung Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1007\/s40291-017-0290-z","article-title":"Significant improvement in detecting BRAF, KRAS, and EGFR mutations using next-generation sequencing as compared with FDA-cleared kits","volume":"21","author":"Ma","year":"2017","journal-title":"Mol. Diagn. Ther."},{"key":"ref_27","first-page":"3647","article-title":"Targeted next-generation sequencing in cytology specimens for molecular profiling of lung adenocarcinoma","volume":"11","author":"Zhang","year":"2018","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1007\/s00428-012-1219-x","article-title":"Optimized algorithm for Sanger sequencing-based EGFR mutation analyses in NSCLC biopsies","volume":"460","author":"Warth","year":"2012","journal-title":"Virchows Arch."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"13","DOI":"10.3349\/ymj.2018.59.1.13","article-title":"Detection of rare mutations in EGFR-ARMS-PCR-negative lung adenocarcinoma by sanger sequencing","volume":"59","author":"Liang","year":"2018","journal-title":"Yonsei Med. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"602726","DOI":"10.3389\/pore.2021.602726","article-title":"Mutation spectrum of EGFR from 21,324 Chinese patients with non-small cell lung cancer (NSCLC) successfully tested by multiple methods in a CAP-accredited laboratory","volume":"27","author":"Mao","year":"2021","journal-title":"Pathol. Oncol. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"10743","DOI":"10.3402\/jom.v4i0.10743","article-title":"Pyrosequencing as a tool for better understanding of human microbiomes","volume":"4","author":"Siqueira","year":"2012","journal-title":"J. Oral. Microbiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/978-1-4939-3360-0_5","article-title":"Digital PCR: Principles and applications","volume":"1392","year":"2016","journal-title":"Methods Mol. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"67810","DOI":"10.18632\/oncotarget.18866","article-title":"Evaluation of digital PCR for detecting low-level EGFR mutations in advanced lung adenocarcinoma patients: A cross-platform comparison study","volume":"8","author":"Gu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1093\/annonc\/mdz046","article-title":"Ultra-deep next-generation sequencing of plasma cell-free DNA in patients with advanced lung cancers: Results from the Actionable Genome Consortium","volume":"30","author":"Li","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1016\/j.annonc.2020.07.014","article-title":"Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: A report from the ESMO Precision Medicine Working Group","volume":"31","author":"Mosele","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"S208","DOI":"10.1016\/j.jtho.2021.01.112","article-title":"FP07.12 underdiagnosis of EGFR exon 20 insertion mutation variants: Estimates from NGS-based real-world datasets","volume":"16","author":"Bauml","year":"2021","journal-title":"J. Thorac. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1016\/j.ccell.2021.10.012","article-title":"Structure-based classification of EGFR mutations informs inhibitor selection for lung cancer therapy","volume":"39","author":"Yenerall","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1080\/15384047.2016.1139235","article-title":"Compound EGFR mutation is frequently detected with co-mutations of actionable genes and associated with poor clinical outcome in lung adenocarcinoma","volume":"17","author":"Kim","year":"2016","journal-title":"Cancer Biol. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e141","DOI":"10.1016\/j.cllc.2020.09.009","article-title":"Inter- and intratumor heterogeneity of EGFR compound mutations in non-small cell lung cancers: Analysis of five cases","volume":"22","author":"Suda","year":"2021","journal-title":"Clin. Lung Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"100007","DOI":"10.1016\/j.xcrm.2020.100007","article-title":"Clonal evolution and heterogeneity of osimertinib acquired resistance mechanisms in EGFR mutant lung cancer","volume":"1","author":"Roper","year":"2020","journal-title":"Cell Rep. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.2147\/OTT.S66502","article-title":"Tumor heterogeneity and resistance to EGFR-targeted therapy in advanced nonsmall cell lung cancer: Challenges and perspectives","volume":"7","author":"Cheng","year":"2014","journal-title":"Onco Targets Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"255","DOI":"10.3390\/curroncol29010024","article-title":"Uncommon EGFR compound mutations in non-small cell lung cancer (NSCLC): A systematic review of available evidence","volume":"29","author":"Attili","year":"2022","journal-title":"Curr. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s40880-018-0321-0","article-title":"First-generation EGFR tyrosine kinase inhibitor therapy in 106 patients with compound EGFR-mutated lung cancer: A single institution\u2019s clinical practice experience","volume":"38","author":"Yu","year":"2018","journal-title":"Cancer Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1097\/JTO.0b013e3181e8b3c5","article-title":"Complex mutations in the epidermal growth factor receptor gene in non-small cell lung cancer","volume":"5","author":"Hata","year":"2010","journal-title":"J. Thorac. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.lungcan.2016.01.018","article-title":"EGFR tyrosine kinase inhibitor (TKI) in patients with advanced non-small cell lung cancer (NSCLC) harboring uncommon EGFR mutations: A real-world study in China","volume":"96","author":"Xu","year":"2016","journal-title":"Lung Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1097\/JTO.0b013e3182614a9d","article-title":"Clinicopathological characteristics of 11 NSCLC patients with EGFR-exon 20 mutations","volume":"7","author":"Kleinberg","year":"2012","journal-title":"J. Thorac. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.jtho.2015.12.107","article-title":"Examining treatment outcomes with erlotinib in patients with advanced non-small cell lung cancer whose tumors harbor uncommon EGFR mutations","volume":"11","author":"Klughammer","year":"2016","journal-title":"J. Thorac. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1080\/00325481.2019.1585690","article-title":"The prognostic impact of TP53 comutation in EGFR mutant lung cancer patients: A systematic review and meta-analysis","volume":"131","author":"Zhang","year":"2019","journal-title":"Postgrad. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"610923","DOI":"10.3389\/fonc.2020.610923","article-title":"Concurrent genetic alterations and other biomarkers predict treatment efficacy of EGFR-TKIs in EGFR-mutant non-small cell lung cancer: A review","volume":"10","author":"Guo","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e216","DOI":"10.1016\/j.cllc.2019.12.003","article-title":"Tyrosine kinase inhibitors for the treatment of EGFR mutation-positive non-small-cell lung cancer: A clash of the generations","volume":"21","author":"Shah","year":"2020","journal-title":"Clin. Lung Cancer"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"LMT43","DOI":"10.2217\/lmt-2020-0011","article-title":"Efficacy and safety of tyrosine kinase inhibitors in advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutation: A network meta-analysis","volume":"10","author":"Alanazi","year":"2020","journal-title":"Lung Cancer Manag."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1097\/JTO.0b013e3181f1c7b0","article-title":"Erlotinib in advanced non-small cell lung cancer: Efficacy and safety findings of the global phase IV Tarceva Lung Cancer Survival Treatment study","volume":"5","author":"Reck","year":"2010","journal-title":"J. Thorac. Oncol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1056\/NEJMoa050753","article-title":"Erlotinib in previously treated non-small-cell lung cancer","volume":"353","author":"Shepherd","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/S1470-2045(11)70184-X","article-title":"Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study","volume":"12","author":"Zhou","year":"2011","journal-title":"Lancet Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/bjc.2013.721","article-title":"First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: A phase-IV, open-label, single-arm study","volume":"110","author":"Douillard","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1200\/JCO.2008.18.7658","article-title":"First-line gefitinib for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy","volume":"27","author":"Inoue","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1056\/NEJMoa0810699","article-title":"Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma","volume":"361","author":"Mok","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1016\/S1470-2045(17)30608-3","article-title":"Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): A randomised, open-label, phase 3 trial","volume":"18","author":"Wu","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1093\/annonc\/mdw611","article-title":"Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: Overall survival data from the phase IIb LUX-Lung 7 trial","volume":"28","author":"Tan","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_60","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_61","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1200\/JCO.19.00931","article-title":"Osimertinib for patients with non-small-cell lung cancer harboring uncommon EGFR mutations: A multicenter, open-label, phase II trial (KCSG-LU15-09)","volume":"38","author":"Cho","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.annonc.2022.02.225","article-title":"Treatment outcome of atypical EGFR mutations in the German National Network Genomic Medicine Lung Cancer (nNGM)","volume":"33","author":"Janning","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.lungcan.2019.02.001","article-title":"Efficacy and long-term survival of advanced lung adenocarcinoma patients with uncommon EGFR mutations treated with 1st generation EGFR-TKIs compared with chemotherapy as first-line therapy","volume":"130","author":"Li","year":"2019","journal-title":"Lung Cancer"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11523-021-00859-6","article-title":"A phase IIIb open-label, single-arm study of afatinib in EGFR TKI-naive patients with EGFRm+ NSCLC: Final analysis, with a focus on patients enrolled at sites in China","volume":"17","author":"Tu","year":"2022","journal-title":"Target Oncol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/j.jtho.2019.12.126","article-title":"Afatinib for the treatment of NSCLC harboring uncommon EGFR mutations: A database of 693 cases","volume":"15","author":"Yang","year":"2020","journal-title":"J. Thorac. Oncol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"5757","DOI":"10.21873\/anticanres.14592","article-title":"Treatment of patients with non-small-cell lung cancer with uncommon EGFR mutations in clinical practice","volume":"40","author":"Yamada","year":"2020","journal-title":"Anticancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"FDA (2018). New indication approved for Afatinib in NSCLC. Oncol. Times, 40, 18.","DOI":"10.1097\/01.COT.0000530901.33684.e4"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2298","DOI":"10.1158\/1535-7163.MCT-20-0103","article-title":"Osimertinib, an irreversible next-generation EGFR tyrosine kinase inhibitor, exerts antitumor activity in various preclinical NSCLC models harboring the uncommon EGFR mutations G719X or L861Q or S768I","volume":"19","author":"Lim","year":"2020","journal-title":"Mol. Cancer Ther."},{"key":"ref_69","first-page":"100459","article-title":"Osimertinib in NSCLC with atypical EGFR-activating mutations: A retrospective multicenter study","volume":"4","author":"Ji","year":"2023","journal-title":"JTO Clin. Res. Rep."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3076","DOI":"10.1200\/JCO.2009.27.9414","article-title":"Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: Results of a phase II trial in patients with advanced non-small-cell lung cancer","volume":"28","author":"Sequist","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1634\/theoncologist.2015-0073","article-title":"Afatinib in non-small cell lung cancer harboring uncommon EGFR mutations pretreated with reversible EGFR inhibitors","volume":"20","author":"Heigener","year":"2015","journal-title":"Oncologist"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"331","DOI":"10.21037\/tlcr.2016.06.04","article-title":"Kinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: Moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements","volume":"5","author":"Costa","year":"2016","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"5305","DOI":"10.1158\/1078-0432.CCR-15-1046","article-title":"EGFR exon 18 mutations in lung cancer: Molecular predictors of augmented sensitivity to afatinib or neratinib as compared with first- or third-generation TKIs","volume":"21","author":"Kobayashi","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.1093\/annonc\/mdy401","article-title":"Programmed death-ligand 1 expression in uncommon epidermal growth factor receptor mutation-positive non-small-cell lung cancer","volume":"29","author":"Taniguchi","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3470","DOI":"10.1158\/1078-0432.CCR-11-2353","article-title":"Clinical outcomes in non-small cell lung cancers harboring different exon 19 deletions in EGFR","volume":"18","author":"Chung","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.ejca.2020.10.005","article-title":"Clinical impact of uncommon epidermal growth factor receptor exon 19 insertion-deletion variants on epidermal growth factor receptor-tyrosine kinase inhibitor efficacy in non-small-cell lung cancer","volume":"141","author":"Peng","year":"2020","journal-title":"Eur. J. Cancer"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1158\/1078-0432.CCR-11-2361","article-title":"EGFR exon 19 insertions: A new family of sensitizing EGFR mutations in lung adenocarcinoma","volume":"18","author":"He","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.annonc.2022.02.003","article-title":"ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer","volume":"33","author":"Passaro","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/s41392-019-0038-9","article-title":"Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer","volume":"4","author":"Vyse","year":"2019","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_80","first-page":"100051","article-title":"EGFR-A763_Y764insFQEA is a unique exon 20 insertion mutation that displays sensitivity to approved and in-development lung cancer EGFR tyrosine kinase inhibitors","volume":"1","author":"Vasconcelos","year":"2020","journal-title":"JTO Clin. Res. Rep."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.lungcan.2018.11.039","article-title":"Efficacy of afatinib or osimertinib plus cetuximab combination therapy for non-small-cell lung cancer with EGFR exon 20 insertion mutations","volume":"127","author":"Hasegawa","year":"2019","journal-title":"Lung Cancer"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1200\/JCO.21.01113","article-title":"Poziotinib for patients with HER2 exon 20 mutant non-small-cell lung cancer: Results from a phase II trial","volume":"40","author":"Elamin","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1016\/j.ccell.2022.06.006","article-title":"Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity","volume":"40","author":"Elamin","year":"2022","journal-title":"Cancer Cell"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.ejca.2021.02.038","article-title":"Poziotinib for EGFR and HER2 exon 20 insertion mutation in advanced NSCLC: Results from the expanded access program","volume":"149","author":"Prelaj","year":"2021","journal-title":"Eur. J. Cancer"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"e214761","DOI":"10.1001\/jamaoncol.2021.4761","article-title":"Treatment outcomes and safety of mobocertinib in platinum-pretreated patients with EGFR exon 20 insertion-positive metastatic non-small cell lung cancer: A phase 1\/2 open-label nonrandomized clinical trial","volume":"7","author":"Zhou","year":"2021","journal-title":"JAMA Oncol."},{"key":"ref_86","unstructured":"FDA (2022, April 10). FDA Grants Accelerated Approval to Mobocertinib for Metastatic Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations, Available online: https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/fda-grants-accelerated-approval-mobocertinib-metastatic-non-small-cell-lung-cancer-egfr-exon-20."},{"key":"ref_87","unstructured":"FDA (2022, April 10). FDA Approves First Targeted Therapy for Subset of Non-Small Cell Lung Cancer, Available online: https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-approves-first-targeted-therapy-subset-non-small-cell-lung-cancer."},{"key":"ref_88","unstructured":"European Medicines Agency (2022, April 10). Rybrevant. Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/rybrevant."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3391","DOI":"10.1200\/JCO.21.00662","article-title":"Amivantamab in EGFR Exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: Initial results from the CHRYSALIS phase I study","volume":"39","author":"Park","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.lungcan.2023.02.008","article-title":"Management of infusion-related reactions (IRRs) in patients receiving amivantamab in the CHRYSALIS study","volume":"178","author":"Park","year":"2023","journal-title":"Lung Cancer"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"S874","DOI":"10.1016\/j.jtho.2021.08.083","article-title":"OA15.02 phase 1 studies of DZD9008, an oral selective EGFR\/HER2 inhibitor in advanced NSCLC with EGFR Exon20 insertion mutations","volume":"16","author":"Janne","year":"2021","journal-title":"J. Thor. Oncol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"S754","DOI":"10.1016\/j.annonc.2020.08.1659","article-title":"1345P\u2014Preliminary safety and activity of CLN-081 in NSCLC with EGFR exon 20 insertion mutations (Ins20)","volume":"31","author":"Piotrowska","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"S1142","DOI":"10.1016\/j.annonc.2020.08.2294","article-title":"LBA61\u2014First analysis of RAIN-701: Study of tarloxotinib in patients with non-small cell lung cancer (NSCLC) EGFR Exon 20 insertion, HER2-activating mutations & other solid tumours with NRG1\/ERBB gene fusions","volume":"31","author":"Liu","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1097\/JTO.0b013e318227e8c6","article-title":"Activity of epidermal growth factor receptor-tyrosine kinase inhibitors in patients with non-small cell lung cancer harboring rare epidermal growth factor receptor mutations","volume":"6","author":"Toffalorio","year":"2011","journal-title":"J. Thorac. Oncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.lungcan.2017.12.002","article-title":"Uncommon mutations in epidermal growth factor receptor and response to first and second generation tyrosine kinase inhibitors: A case series and literature review","volume":"115","author":"Galli","year":"2018","journal-title":"Lung Cancer"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.lungcan.2013.01.018","article-title":"Uncommon epidermal growth factor receptor mutations in non-small cell lung cancer and their mechanisms of EGFR tyrosine kinase inhibitors sensitivity and resistance","volume":"80","author":"Massarelli","year":"2013","journal-title":"Lung Cancer"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Zeng, Y., Guo, T., Zhou, Y., Zhao, Y., Chu, L., Chu, X., Yang, X., Ni, J., and Zhu, Z. (2022). Clinical outcomes of advanced non-small cell lung cancer patients harboring distinct subtypes of EGFR mutations and receiving first-line tyrosine kinase inhibitors: Brain metastasis and de novo T790M matters. BMC Cancer, 22.","DOI":"10.1186\/s12885-022-09245-5"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1056\/NEJMoa1713137","article-title":"Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer","volume":"378","author":"Soria","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"100115","DOI":"10.1016\/j.esmoop.2021.100115","article-title":"A multicenter cohort study of osimertinib compared with afatinib as first-line treatment for EGFR-mutated non-small-cell lung cancer from practical dataset: CJLSG1903","volume":"6","author":"Ito","year":"2021","journal-title":"ESMO Open"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"224","DOI":"10.3389\/fonc.2020.00224","article-title":"Tyrosine kinase inhibitors could be effective against non-small cell lung cancer brain metastases harboring uncommon EGFR mutations","volume":"10","author":"Ma","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"3407","DOI":"10.1111\/1759-7714.14222","article-title":"Efficacy of dacomitinib in patients with EGFR-mutated NSCLC and brain metastases","volume":"12","author":"Zhang","year":"2021","journal-title":"Thorac. Cancer"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.lungcan.2020.12.008","article-title":"Dacomitinib induces objective responses in metastatic brain lesions of patients with EGFR-mutant non-small-cell lung cancer: A brief report","volume":"152","author":"Peng","year":"2021","journal-title":"Lung Cancer"},{"key":"ref_103","unstructured":"(2023, March 16). CLN-081 Produces Antitumor Activity With Acceptable Safety in Heavily Pretreated EGFR Exon 20 Insertion+ NSCLC. Available online: https:\/\/www.onclive.com\/view\/cln-081-produces-antitumor-activity-with-acceptable-safety-in-heavily-pretreated-egfr-exon-20-insertion-nsclc."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"9099","DOI":"10.1200\/JCO.2022.40.16_suppl.9099","article-title":"Mobocertinib (TAK-788) in EGFR exon 20 insertion (ex20ins)+ metastatic non\u2013small cell lung cancer (mNSCLC): Treatment (tx) beyond progressive disease (PD) in platinum-pretreated patients (pts) with and without intracranial PD","volume":"40","author":"Janne","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1080\/14737140.2022.2016397","article-title":"Amivantamab for the treatment of EGFR exon 20 insertion mutant non-small cell lung cancer","volume":"22","author":"Vyse","year":"2022","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Shu, C.A., Goto, K., Cho, B.C., Griesinger, F., Yang, J.C.H., Felip, E., Xie, J., Chen, J., Mahoney, J., and Thayu, M. (2021). CHRYSALIS-2: A phase 1\/1b study of lazertinib as monotherapy and in combination with amivantamab in patients with EGFR-mutant NSCLC. J. Clin. Oncol., 39.","DOI":"10.1200\/JCO.2021.39.15_suppl.TPS9132"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1093\/annonc\/mdz141","article-title":"EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer","volume":"30","author":"Hastings","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e1356145","DOI":"10.1080\/2162402X.2017.1356145","article-title":"EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer","volume":"6","author":"Dong","year":"2017","journal-title":"Oncoimmunology"},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Kapoor, S.S., and Zaiss, D.M.W. (2021). Emerging role of EGFR mutations in creating an immune suppressive tumour microenvironment. Biomedicines, 10.","DOI":"10.3390\/biomedicines10010052"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S1470-2045(18)30144-X","article-title":"Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): An open-label, single-arm, phase 2 study","volume":"19","author":"Garassino","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1158\/1078-0432.CCR-19-2027","article-title":"Impact of EGFR-TKI Treatment on the tumor immune microenvironment in EGFR mutation-positive non-small cell lung cancer","volume":"26","author":"Isomoto","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"100253","DOI":"10.1016\/j.esmoop.2021.100253","article-title":"The immune microenvironment in EGFR- and ERBB2-mutated lung adenocarcinoma","volume":"6","author":"Kirchner","year":"2021","journal-title":"ESMO Open"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.cllc.2020.12.015","article-title":"Subtypes of EGFR- and HER2-mutant metastatic NSCLC influence response to immune checkpoint inhibitors","volume":"22","author":"Lau","year":"2021","journal-title":"Clin. Lung Cancer"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"16122","DOI":"10.1038\/s41598-021-95628-w","article-title":"Comparison of the outcome between immunotherapy alone or in combination with chemotherapy in EGFR-mutant non-small cell lung cancer","volume":"11","author":"Shen","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1093\/annonc\/mdz167","article-title":"Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: Results from the IMMUNOTARGET registry","volume":"30","author":"Mazieres","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1002\/cam4.2037","article-title":"Retrospective efficacy analysis of immune checkpoint inhibitors in patients with EGFR-mutated non-small cell lung cancer","volume":"8","author":"Yamada","year":"2019","journal-title":"Cancer Med."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1111\/1759-7714.13057","article-title":"Comparison of a combination of chemotherapy and immune checkpoint inhibitors and immune checkpoint inhibitors alone for the treatment of advanced and metastatic non-small cell lung cancer","volume":"10","author":"Kuo","year":"2019","journal-title":"Thorac. Cancer"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/S2213-2600(19)30084-0","article-title":"Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): Key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial","volume":"7","author":"Reck","year":"2019","journal-title":"Lancet Respir. Med."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"S754","DOI":"10.1016\/j.annonc.2020.08.1607","article-title":"1293P\u2014IMpower150: Updated efficacy analysis in patients with EGFR mutations","volume":"31","author":"Reck","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.jtho.2021.09.014","article-title":"IMpower150 final exploratory analyses for atezolizumab plus bevacizumab and chemotherapy in key NSCLC patient subgroups with EGFR mutations or metastases in the liver or brain","volume":"17","author":"Nogami","year":"2022","journal-title":"J. Thorac. Oncol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s12943-018-0777-1","article-title":"Management of acquired resistance to EGFR TKI-targeted therapy in advanced non-small cell lung cancer","volume":"17","author":"Wu","year":"2018","journal-title":"Mol. Cancer"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1080\/14740338.2020.1753697","article-title":"Safety of EGFR-TKIs for EGFR mutation-positive non-small cell lung cancer","volume":"19","author":"Zhou","year":"2020","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"2805","DOI":"10.1002\/ijc.30691","article-title":"Comparison of gefitinib, erlotinib and afatinib in non-small cell lung cancer: A meta-analysis","volume":"140","author":"Yang","year":"2017","journal-title":"Int. J. Cancer"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/S1470-2045(16)30033-X","article-title":"Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): A phase 2B, open-label, randomised controlled trial","volume":"17","author":"Park","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"2905","DOI":"10.2217\/fon-2019-0346","article-title":"Sequential afatinib and osimertinib in patients with EGFR mutation-positive non-small-cell lung cancer: Updated analysis of the observational GioTag study","volume":"15","author":"Hochmair","year":"2019","journal-title":"Future Oncol."},{"key":"ref_126","unstructured":"CCO (2023, March 16). CHRYSALIS-2: Update of Amivantamab + Lazertinib in EGFR-Mutant NSCLC After Progression on Osimertinib and Chemotherapy. Available online: https:\/\/clinicaloptions.com\/CE-CME\/chrysalis-2-update\/100003234."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/10\/8878\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:36:35Z","timestamp":1760124995000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/10\/8878"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,17]]},"references-count":126,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["ijms24108878"],"URL":"https:\/\/doi.org\/10.3390\/ijms24108878","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,17]]}}}