{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T18:13:13Z","timestamp":1791655993445,"version":"4.3.4"},"reference-count":14,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"14","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["JCO"],"published-print":{"date-parts":[[2023,5,10]]},"abstract":"<jats:sec>\n                    <jats:title>PURPOSE<\/jats:title>\n                    <jats:p>No approved targeted therapy for the treatment of patients with neuroblastoma RAS viral (v-ras) oncogene homolog ( NRAS)\u2013mutant melanoma is currently available.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>PATIENTS AND METHODS<\/jats:title>\n                    <jats:p>In this phase Ib escalation\/expansion study (ClinicalTrials.gov identifier: NCT02974725 ), the safety, tolerability, and preliminary antitumor activity of naporafenib (LXH254), a BRAF\/CRAF protein kinases inhibitor, were explored in combination with trametinib in patients with advanced\/metastatic KRAS- or BRAF-mutant non\u2013small-cell lung cancer (escalation arm) or NRAS-mutant melanoma (escalation and expansion arms).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Thirty-six and 30 patients were enrolled in escalation and expansion, respectively. During escalation, six patients reported grade \u22653 dose-limiting toxicities, including dermatitis acneiform (n = 2), maculopapular rash (n = 2), increased lipase (n = 1), and Stevens-Johnson syndrome (n = 1). The recommended doses for expansion were naporafenib 200 mg twice a day plus trametinib 1 mg once daily and naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. During expansion, all 30 patients experienced a treatment-related adverse event, the most common being rash (80%, n = 24), blood creatine phosphokinase increased, diarrhea, and nausea (30%, n = 9 each). In expansion, the objective response rate, median duration of response, and median progression-free survival were 46.7% (95% CI, 21.3 to 73.4; 7 of 15 patients), 3.75 (95% CI, 1.97 to not estimable [NE]) months, and 5.52 months, respectively, in patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily, and 13.3% (95% CI, 1.7 to 40.5; 2 of 15 patients), 3.75 (95% CI, 2.04 to NE) months, and 4.21 months, respectively, in patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>Naporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS-mutant melanoma. Prophylactic strategies aimed to lower the incidence of skin-related events are under investigation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1200\/jco.22.02018","type":"journal-article","created":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T15:59:12Z","timestamp":1679500752000},"page":"2651-2660","update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":61,"title":["Initial Evidence for the Efficacy of Naporafenib in Combination With Trametinib in\n                    <i>NRAS<\/i>\n                    -Mutant Melanoma: Results From the Expansion Arm of a Phase Ib, Open-Label Study"],"prefix":"10.1200","volume":"41","clinical-trial-number":[{"clinical-trial-number":"nct02974725","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Filippo","family":"de Braud","sequence":"first","affiliation":[{"name":"Department of Oncology and Hematology-Oncology, University of Milan, Milan, Italy"},{"name":"Medical Oncology and Hematology Department, Istituto Nazionale dei Tumori, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Dooms","sequence":"additional","affiliation":[{"name":"University Hospitals Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7397-2009","authenticated-orcid":false,"given":"Rebecca S.","family":"Heist","sequence":"additional","affiliation":[{"name":"Cancer Center, Massachusetts General Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5854-7290","authenticated-orcid":false,"given":"Celeste","family":"Lebbe","sequence":"additional","affiliation":[{"name":"Department of Dermato-Oncology and CIC, AP-HP H\u00f4pital Saint Louis, Universit\u00e9 Paris Cit\u00e9, Inserm U976, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4844-4087","authenticated-orcid":false,"given":"Martin","family":"Wermke","sequence":"additional","affiliation":[{"name":"NCT\/UCC Early Clinical Trial Unit, Technical University Dresden, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anas","family":"Gazzah","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Thoracic Cancer Group, Gustave Roussy Cancer Institute, Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3524-7858","authenticated-orcid":false,"given":"Dirk","family":"Schadendorf","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Hospital Essen & German Cancer Consortium, Partner Site Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8920-5429","authenticated-orcid":false,"given":"Piotr","family":"Rutkowski","sequence":"additional","affiliation":[{"name":"Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8833-8812","authenticated-orcid":false,"given":"J\u00fcrgen","family":"Wolf","sequence":"additional","affiliation":[{"name":"Center for Integrated Oncology, Department of Internal Medicine, University Hospital Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8322-475X","authenticated-orcid":false,"given":"Paolo A.","family":"Ascierto","sequence":"additional","affiliation":[{"name":"Melanoma and Cancer Immunotherapy Unit, Istituto Nazionale Tumori IRCCS Fondazione G. 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