{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T07:03:05Z","timestamp":1784530985228,"version":"3.55.0"},"reference-count":116,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"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>Non-small cell lung cancer (NSCLC) comprises a diverse group of malignancies driven by distinct molecular alterations that have become critical targets for precision oncology. Among these, EGFR exon 20 insertion mutations and HER2 dysregulation, including HER2 mutations, amplification, and overexpression, define clinically important subsets of NSCLC characterized by unique biological behavior and historically limited treatment options. Although these alterations account for a relatively small proportion of NSCLC cases, their identification has become increasingly relevant due to advances in molecular diagnostics and the development of novel targeted therapies. This review provides a comprehensive overview of the epidemiology, molecular biology, and clinical characteristics of EGFR exon 20 insertion-mutated and HER2-deregulated NSCLC. We discuss current diagnostic approaches, including the role of next-generation sequencing and biomarker testing, and summarize the evolving therapeutic landscape encompassing conventional chemotherapy, immunotherapy, and targeted agents. Particular attention is given to recently approved therapies and emerging treatment strategies, including tyrosine kinase inhibitors and antibody-based therapies that have demonstrated clinically meaningful activity in these patient populations. We also address the major challenges associated with treatment resistance, molecular heterogeneity, and optimal therapeutic sequencing. Finally, we highlight ongoing research efforts and future perspectives aimed at improving outcomes for patients with these rare but clinically significant molecular subtypes of NSCLC.<\/jats:p>","DOI":"10.3390\/cancers18142334","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T06:09:09Z","timestamp":1784527749000},"page":"2334","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["New Treatment Strategies for Rare Genomic Alterations: EGFR Exon 20 Insertions and HER2-Deregulated Lung Cancer"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1659-788X","authenticated-orcid":false,"given":"Lodovica","family":"Zullo","sequence":"first","affiliation":[{"name":"Gustave Roussy, Department of Cancer Medicine, University of Paris Saclay, 94805 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9462-875X","authenticated-orcid":false,"given":"Jordi","family":"Remon","sequence":"additional","affiliation":[{"name":"Gustave Roussy, Department of Cancer Medicine, University of Paris Saclay, 94805 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1097\/JTO.0b013e3182779d18","article-title":"Natural History and Molecular Characteristics of Lung Cancers Harboring EGFR Exon 20 Insertions","volume":"8","author":"Oxnard","year":"2013","journal-title":"J. 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