{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T07:25:01Z","timestamp":1787901901435,"version":"build-2784847793"},"reference-count":28,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"14","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["J Clin Oncol"],"published-print":{"date-parts":[[2026,5,10]]},"abstract":"<jats:sec>\n                    <jats:title>PURPOSE<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">BRAF<\/jats:italic>\n                      V600 mutations are tumor-agnostic oncogenic drivers whose targeted inhibition is challenged by therapeutic resistance. Mosperafenib is a novel paradox breaker and brain-penetrant BRAF inhibitor (BRAFi), tested in this study for safety, maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary clinical activity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>PATIENTS AND METHODS<\/jats:title>\n                    <jats:p>\n                      This phase Ia\/b study was conducted in patients with advanced solid tumors harboring a\n                      <jats:italic toggle=\"yes\">BRAF<\/jats:italic>\n                      V600 mutation (ISRCTN13713551). The modified continuous reassessment method guided dose escalation of mosperafenib, which was given orally up to 3,600 mg once daily in 28-day cycles. The primary objective was to estimate the MTD and\/or recommended phase II dose(s).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Eighty patients (60% BRAFi-exposed)\u201463 with colorectal cancer (CRC), 13 with melanoma, and 4 with other solid tumors\u2014received \u22651 dose of mosperafenib as a single agent for a median of 3.7 months (range, 0.2-28.6). Two dose-limiting grade 3 toxicities of rash and rash maculopapular were reported. MTD was not reached. Grade 3 to 4 treatment-related adverse events (TRAEs) occurred in 13 patients (16.3%); no grade 5 TRAEs events were reported. Two patients (2.5%) discontinued study treatment due to TRAEs. There were no reports of palmar-plantar erythrodysesthesia or keratoacanthoma. Linear and time-independent PK was demonstrated across the tested dose range, achieving exposure levels with sustained PK-derived pERK inhibition \u226590%. An exposure-response relationship was observed. Overall response rate was 24.2%, including two complete responses and 14 partial responses. Median progression-free survival was 6.4 months in patients with CRC (200 mg once daily-1200 mg three times a day) and 3.5 months in patients with melanoma (200 mg once daily-800 mg twice a day).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>Mosperafenib demonstrated a favorable safety profile, sustained target inhibition, and early signs of clinically meaningful single-agent activity in BRAFi-na\u00efve and BRAFi-exposed patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1200\/jco-25-02444","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T19:59:25Z","timestamp":1774641565000},"page":"1337-1348","update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":5,"title":["Phase I Study of Mosperafenib, a Novel Paradox Breaker B-Raf Proto-Oncogene Serine\/Threonine Kinase (BRAF) Inhibitor, in Patients With\n                    <i>BRAF<\/i>\n                    V600\u2013Mutant Solid Tumors"],"prefix":"10.1200","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7531-343X","authenticated-orcid":false,"given":"Maria","family":"Vieito","sequence":"first","affiliation":[{"name":"Vall d'Hebron University Hospital, Universidad Autonoma de Barcelona, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4991-9355","authenticated-orcid":false,"given":"Elisa","family":"Fontana","sequence":"additional","affiliation":[{"name":"Sarah Cannon Research Institute, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1016-3113","authenticated-orcid":false,"given":"Catherine H.","family":"Han","sequence":"additional","affiliation":[{"name":"New Zealand Clinical Research and Auckland City Hospital, Auckland, New 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