{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T19:24:46Z","timestamp":1793042686646,"version":"4.5.0"},"reference-count":25,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,6,29]],"date-time":"2020-06-29T00:00:00Z","timestamp":1593388800000},"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>This study investigated the efficacy and safety of pimasertib (MEK1\/MEK2 inhibitor) versus dacarbazine (DTIC) in patients with untreated NRAS-mutated melanoma. Phase II, multicenter, open-label trial. Patients with unresectable, stage IIIc\/IVM1 NRAS-mutated cutaneous melanoma were randomized 2:1 to pimasertib (60 mg; oral twice-daily) or DTIC (1000 mg\/m2; intravenously) on Day 1 of each 21-day cycle. Patients progressing on DTIC could crossover to pimasertib. Primary endpoint: investigator-assessed progression-free survival (PFS); secondary endpoints: overall survival (OS), objective response rate (ORR), quality of life (QoL), and safety. Overall, 194 patients were randomized (pimasertib n = 130, DTIC n = 64), and 191 received treatment (pimasertib n = 130, DTIC n = 61). PFS was significantly improved with pimasertib versus DTIC (median 13 versus 7 weeks, respectively; hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.42\u20130.83; p = 0.0022). ORR was improved with pimasertib (odds ratio 2.24, 95% CI 1.00\u20134.98; p = 0.0453). OS was similar between treatments (median 9 versus 11 months, respectively; HR 0.89, 95% CI 0.61\u20131.30); 64% of patients receiving DTIC crossed over to pimasertib. Serious adverse events (AEs) were more frequent for pimasertib (57%) than DTIC (20%). The most common treatment-emergent AEs were diarrhea (82%) and blood creatine phosphokinase (CPK) increase (68%) for pimasertib, and nausea (41%) and fatigue (38%) for DTIC. Most frequent grade \u22653 AEs were CPK increase (34%) for pimasertib and neutropenia (15%) for DTIC. Mean QoL scores (baseline and last assessment) were similar between treatments. Pimasertib has activity in NRAS-mutated cutaneous melanoma and a safety profile consistent with known toxicities of MEK inhibitors. Trial registration: ClinicalTrials.gov, NCT01693068.<\/jats:p>","DOI":"10.3390\/cancers12071727","type":"journal-article","created":{"date-parts":[[2020,6,30]],"date-time":"2020-06-30T09:36:04Z","timestamp":1593509764000},"page":"1727","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Pimasertib Versus Dacarbazine in Patients With Unresectable NRAS-Mutated Cutaneous Melanoma: Phase II, Randomized, Controlled Trial with Crossover"],"prefix":"10.3390","volume":"12","author":[{"given":"Celeste","family":"Lebb\u00e9","sequence":"first","affiliation":[{"name":"AP-HP Dermatology CIC Department, Saint Louis Hospital, and INSERM U976, Universit\u00e9 de Paris, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Dutriaux","sequence":"additional","affiliation":[{"name":"Dermatology, Hopital Saint-Andre\u2014CHU, 33000 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"Lesimple","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Comprehensive Cancer Center Eug\u00e8ne Marquis, 35000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2753-020X","authenticated-orcid":false,"given":"Willem","family":"Kruit","sequence":"additional","affiliation":[{"name":"Internal Oncology, Erasmus MC Cancer Institute, 3008 AE Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Kerger","sequence":"additional","affiliation":[{"name":"Medical Oncology, Institut Jules Bordet, 1000 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1995-2434","authenticated-orcid":false,"given":"Luc","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Centre Hospitalier Lyon Sud, 69310 Pierre B\u00e9nite, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Guillot","sequence":"additional","affiliation":[{"name":"Department of Dermatology, H\u00f4pital Saint Eloi, 34295 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"de Braud","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Istituto Nazionale dei Tumori, Universit\u00e0 degli Studi di Milano, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claus","family":"Garbe","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Hospital T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Jacques","family":"Grob","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Cutaneous Oncology Service, H\u00f4pital de la Timone, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Loquai","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Medical Center Mainz, 55019 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Ferraresi","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology 1, IRCCS \u201cRegina Elena\u201d National Cancer Institute, 00144 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Robert","sequence":"additional","affiliation":[{"name":"Dermatology Department, Institut Gustave Roussy and Paris Sud University, 94800 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Vasey","sequence":"additional","affiliation":[{"name":"Icon Cancer Care, The Wesley Hospital, Auchenflower, QLD 4066, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Conry","sequence":"additional","affiliation":[{"name":"Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Isaacs","sequence":"additional","affiliation":[{"name":"MidCentral Regional Cancer Treatment Service, Palmerston North Hospital, Palmerston North 4442, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrique","family":"Espinosa","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Hospital Universitario La Paz, 28046 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3833-5757","authenticated-orcid":false,"given":"Armin","family":"Schueler","sequence":"additional","affiliation":[{"name":"Global Biostatistics Oncology, Merck KGaA, 64293 Darmstadt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Massimini","sequence":"additional","affiliation":[{"name":"GCDU Oncology, Merck KGaA, 64293 Darmstadt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Dr\u00e9no","sequence":"additional","affiliation":[{"name":"Department of Dermato Cancerology, CIC 1413, CRCINA Inserm 1232, CHU Nantes, 44093 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,29]]},"reference":[{"key":"ref_1","first-page":"488","article-title":"Treatment of metastatic melanoma: An overview","volume":"23","author":"Bhatia","year":"2009","journal-title":"Oncology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1056\/NEJMoa1003466","article-title":"Improved survival with ipilimumab in patients with metastatic melanoma","volume":"363","author":"Hodi","year":"2010","journal-title":"N. 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