{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:13:30Z","timestamp":1760573610661,"version":"build-2065373602"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The neurofibromin 1 (NF1) protein regulates the downstream RAS\/RAF\/MEK\/ERK pathway and functions as a tumor suppressor. Somatic pathogenic mutations in <jats:italic>NF1<\/jats:italic> are found in approximately 4.7%\u201310% of NSCLC, with a higher frequency in lung adenocarcinomas, reaching up to 15% in certain cohorts. Trametinib, a MEK inhibitor, has demonstrated activity in tumors with <jats:italic>NF1<\/jats:italic> alteration in preclinical models, and clinical activity in low-grade glioma and plexiform neurofibromas in neurofibromatosis type 1. Trametinib had only limited clinical efficacy in other tumor types with <jats:italic>NF1<\/jats:italic> mutations in the NCI-Match trial. However, the sole NSCLC patient that was evaluable for response in the NCI-Match trial benefited from a deep partial response. More data for the activity of MEK inhibitors in <jats:italic>NF1<\/jats:italic> altered NSCLC are needed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Cases presentation<\/jats:title><jats:p>We report here a series of four NSCLC patients with <jats:italic>NF1<\/jats:italic> pathogenic mutations treated with trametinib. All patients underwent extensive molecular testing with next-generation sequencing (custom 462-gene panel) and copy number variation analysis and were deemed to have potential <jats:italic>NF1<\/jats:italic>-loss-driven tumors after a case discussion in a multidisciplinary molecular tumor board. Two patients exhibited homozygous <jats:italic>NF1<\/jats:italic> LOF alterations, whereas two patients had heterozygous loss-of-function alterations. All patients were treated with oral trametinib 2 mg once daily, after failure of standard therapies. Trametinib was administered for a maximum duration of 9 weeks. The best response observed was a stable disease in one patient. All patients died within 3 months of treatment initiation. No side effects warranted treatment cessation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In this small case series, NSCLC patients with <jats:italic>NF1<\/jats:italic> alterations did not derive clinical benefit from trametinib. While these data do not support trametinib as a treatment option for <jats:italic>NF1<\/jats:italic>-mutated NSCLC, larger studies are required to draw firm conclusions.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2025.1481284","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T04:23:40Z","timestamp":1760502220000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Trametinib in the treatment of patients with metastatic lung adenocarcinoma harboring NF1 mutation: a case series and literature review"],"prefix":"10.3389","volume":"15","author":[{"given":"Floryane","family":"Kim","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maxime","family":"Borgeaud","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"De 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