{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T03:41:33Z","timestamp":1784864493147,"version":"3.55.0"},"reference-count":59,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T00:00:00Z","timestamp":1772409600000},"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>Over the past decade, significant achievements in elucidating the molecular pathogenesis of non\u2013small cell lung cancer (NSCLC) have catalyzed a paradigm shift from empiric therapies to precision oncology. In this context, HER2 alterations, including protein overexpression, gene amplification, and activating mutations, constitute distinct molecular subsets within NSCLC. In the past few years, targeted therapeutic modalities such as antibody\u2013drug conjugates (ADCs), particularly trastuzumab deruxtecan (the first agent to be granted FDA approval for HER2-mutant NSCLC), alongside selective tyrosine kinase inhibitors (TKIs), including zongertinib and sevabertinib, have demonstrated robust systemic efficacy and notable intracranial penetration. This comprehensive review delineates the molecular landscape and clinical phenotypes of HER2-altered NSCLC, synthesizes interim and mature data from ongoing clinical trials evaluating anti-HER2 therapies, and critically examines efficacy and safety results from different classes of targeted agents. Further research is crucial to uncover potential mechanisms of resistance in NSCLC with HER2 mutations and define sequencing or combinatorial strategies pertinent to optimizing individualized patient management.<\/jats:p>","DOI":"10.3390\/ijms27052334","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T12:39:56Z","timestamp":1772455196000},"page":"2334","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["HER2 Alterations in Non-Small Cell Lung Cancer: Emerging Perspectives on the Therapeutic Landscape"],"prefix":"10.3390","volume":"27","author":[{"given":"Paola","family":"Muscolino","sequence":"first","affiliation":[{"name":"School of Specialization in Medical Oncology, Department of Human Pathology \u201cG. Barresi\u201d, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Fassi","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Candiolo Cancer Institute\u2014FPO\u2014IRCCS, 10060 Candiolo, Italy"},{"name":"Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, ASST Spedali Civili, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Signorelli","sequence":"additional","affiliation":[{"name":"Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, 20162 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8448-4388","authenticated-orcid":false,"given":"Francesca","family":"Colonese","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego Luigi","family":"Cortinovis","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy"},{"name":"Medicine and Surgery Department, University of Milano Bicocca, 20900 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Lo Russo","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Pasello","sequence":"additional","affiliation":[{"name":"Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, 35100 Padova, Italy"},{"name":"Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Infurna","sequence":"additional","affiliation":[{"name":"School of Specialization in Medical Oncology, Department of Human Pathology \u201cG. Barresi\u201d, University of Messina, 98125 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":"Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy"},{"name":"Applied Biology and Experimental Medicine, Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9837-9148","authenticated-orcid":false,"given":"Massimiliano","family":"Berretta","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, \u201cGaetano Martino\u201d Hospital, 98125 Messina, Italy"},{"name":"Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7168-9704","authenticated-orcid":false,"given":"Vanesa","family":"Gregorc","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Candiolo Cancer Institute\u2014FPO\u2014IRCCS, 10060 Candiolo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Lazzari","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Candiolo Cancer Institute\u2014FPO\u2014IRCCS, 10060 Candiolo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariacarmela","family":"Santarpia","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, \u201cGaetano Martino\u201d Hospital, 98125 Messina, Italy"},{"name":"Department of Human Pathology \u201cG. Barresi\u201d, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,2]]},"reference":[{"key":"ref_1","first-page":"e70043","article-title":"Cancer Statistics, 2026","volume":"76","author":"Siegel","year":"2026","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1200\/JCO.21.01626","article-title":"Targeted Therapies for Lung Cancer Patients with Oncogenic Driver Molecular Alterations","volume":"40","author":"Tan","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1016\/j.annonc.2025.06.007","article-title":"Updated Treatment Recommendations for Systemic Treatment: From the ESMO Oncogene-Addicted Metastatic NSCLC Living Guideline","volume":"36","author":"Hendriks","year":"2025","journal-title":"Ann. 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