{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T07:41:23Z","timestamp":1774942883305,"version":"3.50.1"},"reference-count":12,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:p>Invasive cases of melanoma have increased by 44% annually in the past decade. B-Raf serine-threonine kinase (BRAF)\/Mitogen-activated protein kinase kinase (MEK) inhibitors have become the standard of care for stage III\/IV BRAF mutant melanoma. Due to limited adverse event (AE) data based on clinical trials, we aimed to describe and compare the AE and outcomes associated with melanoma therapies. A retrospective disproportionality analysis was conducted to assess and compare the trends of AEs associated with BRAF\/MEK inhibitors and combinations. The primary data were extracted from the Food and Drug Administration (FDA) Adverse Event Reporting System database from 2012 to 2021. Study drugs included BRAF\/MEK inhibitors (dabrafenib, trametinib, vemurafenib, cobimetinib, encorafenib, and binimetinib). A reporting odds ratio (ROR) was calculated for the most common AEs and outcomes reported. We found 195\u2005640 unique AE reports associated with BRAF and MEK inhibitor usage, representing 52 772 patients. The leading AEs associated with BRAFi and MEKi use were as follows: pyrexia, fatigue, nausea, diarrhea, rash, vomiting, and arthralgia. Encorafenib and binimetinib had significant odds for nausea [ROR, 1.91 (1.73\u20132.11) and ROR, 1.91 (1.73\u20132.11), respectively]. The incidence of fatigue was highest in the encorafenib [ROR, 1.71 (1.54\u20131.90)], binimetinib [ROR, 1.74 (1.57\u20131.94)], and vemurafenib [ROR, 1.27 (1.14\u20131.27)] groups. Cobimetinib had significantly increased odds for developing a disability [ROR, 4.95 (4.28\u20135.74)], having a hospitalization [ROR, 2.08 (1.99\u20132.17)], and experiencing a life-threatening event [ROR, 1.78 (1.55\u20132.03)]. AE reports associated with melanoma therapies are sizable and significant. Healthcare professionals should be aware of the AE profiles attributable to the melanoma treatment and management.<\/jats:p>","DOI":"10.1097\/cmr.0000000000001069","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T10:00:13Z","timestamp":1763978413000},"page":"58-63","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":2,"title":["Trends of adverse event reports associated with BRAF and MEK inhibitors and combinations: a retrospective disproportionality analysis using the FDA adverse event reporting system database from 2012 to 2021"],"prefix":"10.1097","volume":"36","author":[{"given":"Kiana R.","family":"Mullins","sequence":"first","affiliation":[{"name":"James L. Winkle College of Pharmacy, University of Cincinnati Academic Health Center, Cincinnati, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeff J.","family":"Guo","sequence":"additional","affiliation":[{"name":"James L. Winkle College of Pharmacy, University of Cincinnati Academic Health Center, Cincinnati, Ohio, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"R2-20251230","doi-asserted-by":"crossref","first-page":"1992880","DOI":"10.1080\/2162402X.2021.1992880","article-title":"Short-term treatment with multi-drug regimens combining BRAF\/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma.","volume":"10","author":"White","year":"2021","journal-title":"Oncoimmunology"},{"key":"R3-20251230","doi-asserted-by":"crossref","first-page":"2373","DOI":"10.1038\/onc.2012.345","article-title":"MAP kinase signaling and inhibition in melanoma.","volume":"32","author":"Sullivan","year":"2013","journal-title":"Oncogene"},{"key":"R4-20251230","doi-asserted-by":"crossref","first-page":"482","DOI":"10.3390\/cancers12020482","article-title":"Current advances in the treatment of BRAF-mutant melanoma.","volume":"12","author":"Patel","year":"2020","journal-title":"Cancers"},{"key":"R5-20251230","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1177\/1758834014566428","article-title":"Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma.","volume":"7","author":"Welsh","year":"2015","journal-title":"Ther Adv Med Oncol"},{"key":"R7-20251230","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1080\/14737140.2020.1724097","article-title":"The potential of BRAF-targeted therapy combined with immunotherapy in melanoma.","volume":"20","author":"Naderi-Azad","year":"2020","journal-title":"Expert Rev Anticancer Ther"},{"key":"R9-20251230","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.3390\/cancers12061650","article-title":"Safety of BRAF+MEK inhibitor combinations: severe adverse event evaluation.","volume":"12","author":"Meirson","year":"2020","journal-title":"Cancers (Basel)"},{"key":"R10-20251230","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1056\/NEJMoa1210093","article-title":"Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.","volume":"367","author":"Flaherty","year":"2012","journal-title":"N Engl J Med"},{"key":"R11-20251230","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.3390\/cancers11121950","article-title":"Efficacy and adverse events in metastatic melanoma patients treated with combination BRAF Plus MEK inhibitors versus BRAF inhibitors: a systematic review.","volume":"11","author":"Greco","year":"2019","journal-title":"Cancers"},{"key":"R12-20251230","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1200\/JCO.2012.43.5966","article-title":"Phase II study of the MEK1\/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor.","volume":"31","author":"Kim","year":"2013","journal-title":"J Clin Oncol"},{"key":"R13-20251230","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1056\/NEJMoa1408868","article-title":"Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.","volume":"371","author":"Larkin","year":"2014","journal-title":"N Engl J Med"},{"key":"R16-20251230","doi-asserted-by":"crossref","first-page":"e000491","DOI":"10.1136\/esmoopen-2019-000491","article-title":"Tolerability of BRAF\/MEK inhibitor combinations: adverse event evaluation and management.","volume":"4","author":"Heinzerling","year":"2019","journal-title":"ESMO Open"},{"key":"R17-20251230","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.3390\/cancers12071819","article-title":"Sex and gender disparities in melanoma.","volume":"12","author":"Bellenghi","year":"2020","journal-title":"Cancers (Basel)"}],"container-title":["Melanoma Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.lww.com\/10.1097\/CMR.0000000000001069","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T17:00:23Z","timestamp":1767114023000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1097\/CMR.0000000000001069"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,25]]},"references-count":12,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026]]}},"URL":"https:\/\/doi.org\/10.1097\/cmr.0000000000001069","relation":{},"ISSN":["0960-8931","1473-5636"],"issn-type":[{"value":"0960-8931","type":"print"},{"value":"1473-5636","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,25]]},"assertion":[{"value":"2022-07-19","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-14","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}