{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T22:45:21Z","timestamp":1788475521825,"version":"build-2803163510"},"reference-count":52,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"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>Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations are the third most common EGFR mutation subtype in non-small cell lung cancer (NSCLC), accounting for approximately 4\u201312% of all EGFR-mutated cases. Unlike classical EGFR mutations, ex20ins mutations confer inherent resistance to first-, second- and third-generation EGFR tyrosine kinase inhibitors (TKIs) due to unique structural alterations that lock the \u03b1C-helix in an active orientation, creating steric hindrance within the drug-binding pocket. Until recently, platinum-based chemotherapy remained the standard first-line treatment, with objective response rates (ORR) of 19\u201347% and a median progression-free survival (PFS) of 6\u20137 months. Over the past five years, the therapeutic landscape has shifted, driven by the development of selective inhibitors and bispecific antibodies. Amivantamab, a bispecific EGFR\u2013mesenchymal\u2013epithelial transition factor (MET) antibody combined with chemotherapy, demonstrated superior efficacy in the PAPILLON trial, with an ORR of 73% and a median PFS of 11.4 months in the first-line setting. Sunvozertinib, an oral, selective EGFR inhibitor, received U.S. Food and Drug Administration (FDA) accelerated approval in 2025, with an ORR of 46% and a median duration of response (DOR) of 11.1 months in platinum-pretreated patients. Emerging therapies, including zipalertinib and furmonertinib, have shown promising results in early-phase trials, with zipalertinib demonstrating activity in patients pretreated with amivantamab (ORR 31.5%) and furmonertinib achieving remarkable responses in treatment-naive patients (ORR 78.6% at 240 mg). This comprehensive review analyzes the molecular biology, structural mechanisms, current therapeutic options, and novel investigational agents for EGFR ex20ins-mutated NSCLC.<\/jats:p>","DOI":"10.3390\/ijms27093714","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T09:01:24Z","timestamp":1776848484000},"page":"3714","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Therapeutic Advances in Non-Small Cell Lung Cancer Harboring EGFR Exon 20 Insertion Mutations: From Molecular Biology to Targeted Therapy"],"prefix":"10.3390","volume":"27","author":[{"given":"Daniel","family":"Rosas","sequence":"first","affiliation":[{"name":"Memorial Cancer Institute, Memorial Healthcare System, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Desai","sequence":"additional","affiliation":[{"name":"Hebert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2669-5771","authenticated-orcid":false,"given":"Luis","family":"Raez","sequence":"additional","affiliation":[{"name":"Memorial Cancer Institute, Memorial Healthcare System, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"key":"ref_1","first-page":"209","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. 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