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BRAF inhibitors have demonstrated efficacy in melanoma. However, their role in non-melanomatous cancers was originally contentious. This systematic review aims to evaluate the safety and efficacy of BRAF-targeted therapies, both as monotherapy and in combination with other targeted therapies, in BRAF-mutated, non-melanomatous tumours.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A systematic search of MEDLINE, PubMed, EMBASE and Cochrane CENTRAL was conducted from January 2010 to January 2025. Eligible studies included prospective and retrospective trials as well as cohort studies assessing BRAF inhibitors in non-melanomatous cancers. Primary outcomes included objective response rate, progression free survival, duration of response and overall survival.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Thirty-six studies comprising 3141 patients were included, spanning over 14 tumour types. The majority (78%) were phase II basket trials. Colorectal (n\u2009=\u20091569, 50%), lung (n\u2009=\u2009756, 24%) and thyroid (n\u2009=\u2009114, 4%) were the most commonly represented tumour types. Combination therapy (e.g., BRAF and MEK inhibition concurrently) demonstrated superior efficacy to monotherapy (e.g. ORR 45\u201351% v 5\u201320% in colorectal cancer), with efficacy varying by histology. Toxicity profiles were consistent with known class effects and higher with more frequent\u2009\u2265\u2009grade 3 adverse events in combination therapy compared with monotherapy. Most studies included exhibited a moderate risk of bias due to single-arm design and lack of randomisation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Although BRAF-targeted therapies have been positioned within the tumour-agnostic paradigm, the available evidence suggests clinically meaningful activity across multiple non-melanomatous BRAF-mutant tumours that is nevertheless modified by tumour lineage, biological context, and treatment strategy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s10147-026-03079-y","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T15:28:41Z","timestamp":1781191721000},"page":"1500-1515","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["BRAF-targeted therapy in non-melanomatous BRAF-mutant tumours: a systematic review of broad but histology-modulated efficacy"],"prefix":"10.1007","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8313-5159","authenticated-orcid":false,"given":"Yael R","family":"Lefkovits","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke S","family":"McLean","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R","family":"Middleton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"3079_CR1","doi-asserted-by":"publisher","first-page":"936","DOI":"10.1016\/j.annonc.2024.07.730","volume":"35","author":"CB Westphalen","year":"2024","unstructured":"Westphalen CB, Martins-Branco D, Beal JR et al (2024) The ESMO tumour-agnostic classifier and screener (ETAC-S): a tool for assessing tumour-agnostic potential of molecularly guided therapies and for steering drug development. 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