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Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan\u2011RAF inhibitor. This first-in-human phase 1 study explored the safety and antitumor activity of tovorafenib.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>This two-part study in adult patients with relapsed or refractory advanced solid tumors included a dose escalation phase and a dose expansion phase including molecularly defined cohorts of patients with melanoma. Primary objectives were to evaluate the safety of tovorafenib administered once every other day (Q2D) or once weekly (QW), and to determine the maximum-tolerated and recommended phase 2 dose (RP2D) on these schedules. Secondary objectives included evaluation of antitumor activity and tovorafenib pharmacokinetics.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Tovorafenib was administered to 149 patients (Q2D <jats:italic>n<\/jats:italic>\u2009=\u2009110, QW <jats:italic>n<\/jats:italic>\u2009=\u200939). The RP2D of tovorafenib was defined as 200\u00a0mg Q2D or 600\u00a0mg QW. In the dose expansion phase, 58 (73%) of 80 patients in Q2D cohorts and 9 (47%) of 19 in the QW cohort had grade\u2009\u2265\u20093 adverse events. The most common of these overall were anemia (14 patients, 14%) and maculo-papular rash (8 patients, 8%). Responses were seen in 10 (15%) of 68 evaluable patients in the Q2D expansion phase, including in 8 of 16 (50%) patients with <jats:italic>BRAF<\/jats:italic> mutation-positive melanoma na\u00efve to RAF and MEK inhibitors. In the QW dose expansion phase, there were no responses in 17 evaluable patients with <jats:italic>NRAS<\/jats:italic> mutation-positive melanoma na\u00efve to RAF and MEK inhibitors; 9 patients (53%) had a best response of stable disease. QW dose administration was associated with minimal accumulation of tovorafenib in systemic circulation in the dose range of 400\u2013800\u00a0mg.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>The safety profile of both schedules was acceptable, with QW dosing at the RP2D of 600\u00a0mg QW preferred for future clinical studies. Antitumor activity of tovorafenib in <jats:italic>BRAF<\/jats:italic>-mutated melanoma was promising and justifies continued clinical development across multiple settings.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>ClinicalTrials.gov identifier<\/jats:title>\n                <jats:p>NCT01425008.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00280-023-04544-5","type":"journal-article","created":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T04:03:16Z","timestamp":1684814596000},"page":"15-28","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Phase 1 study of the pan-RAF inhibitor tovorafenib in patients with advanced solid tumors followed by dose expansion in patients with metastatic melanoma"],"prefix":"10.1007","volume":"92","author":[{"given":"Drew W.","family":"Rasco","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa","family":"Medina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pippa","family":"Corrie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna C.","family":"Pavlick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R.","family":"Middleton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Lorigan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Hebert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Plummer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Larkin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjiv S.","family":"Agarwala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adil I.","family":"Daud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaheng","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviana","family":"Bozon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Kneissl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6890-2444","authenticated-orcid":false,"given":"Elly","family":"Barry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J.","family":"Olszanski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,23]]},"reference":[{"issue":"10","key":"4544_CR1","doi-asserted-by":"publisher","first-page":"1618","DOI":"10.3390\/cancers11101618","volume":"11","author":"C Braicu","year":"2019","unstructured":"Braicu C, Buse M, Busuioc C, Drula R, Gulei D, Raduly L, Rusu A, Irimie A, Atanasov AG, Slaby O, Ionescu C, Berindan-Neagoe I (2019) A comprehensive review on MAPK: a promising therapeutic target in cancer. 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JQ and EB are employees of Day One Biopharmaceuticals. AJO reports personal fees from advisory boards including Merck, BMS, Pfizer, Takeda, Novartis, Eisai, Nektar and InstilBio; institution research support from Adaptimmune, Alkermes, Amgen, Antegene, Astellas, BMS, Checkmate, Eutilex, Fate therapeutics, Gan & Lee, GlycoNex, InstilBio, Intensity, Kadmon, Kartos, Kezar, Kinnate, Nektar, OncoSec, Regeneron, Shionogi, Sound Biologics, Sumitomo Dainippon, Takeda, and Targovax. Other authors did not declare a conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}