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Next-generation pan-RAF dimer inhibitors are limited by a narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling. PF-07799933 \u00b1 binimetinib inhibited growth of mouse xenograft tumors driven by mutant BRAF that functions as dimers and by BRAFV600E with acquired resistance to current RAF inhibitors. We treated patients with treatment-refractory BRAF-mutant solid tumors in a first-in-human clinical trial (NCT05355701) that utilized a novel, flexible, pharmacokinetics-informed dose escalation design that allowed rapid achievement of PF-07799933 efficacious concentrations. PF-07799933 \u00b1 binimetinib was well-tolerated and resulted in multiple confirmed responses, systemically and in the brain, in patients with BRAF-mutant cancer who were refractory to approved RAF inhibitors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>PF-07799933 treatment was associated with antitumor activity against BRAFV600- and non-V600-mutant cancers preclinically and in treatment-refractory patients, and PF-07799933 could be safely combined with a MEK inhibitor. The novel, rapid pharmacokinetics (PK)-informed dose escalation design provides a new paradigm for accelerating the testing of next-generation targeted therapies early in clinical development.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-24-0024","type":"journal-article","created":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T12:47:58Z","timestamp":1714567678000},"page":"1599-1611","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["A Next-Generation BRAF Inhibitor Overcomes Resistance to BRAF Inhibition in Patients with\n                    <i>BRAF<\/i>\n                    -Mutant Cancers Using Pharmacokinetics-Informed Dose Escalation"],"prefix":"10.1158","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7233-5454","authenticated-orcid":false,"given":"Rona","family":"Yaeger","sequence":"first","affiliation":[{"name":"Memorial Sloan Kettering Cancer Center, New York, New York. 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0944-7418","authenticated-orcid":false,"given":"Meredith A.","family":"McKean","sequence":"additional","affiliation":[{"name":"Sarah Cannon Research Institute, Nashville, Tennessee. 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1290-9276","authenticated-orcid":false,"given":"Rizwan","family":"Haq","sequence":"additional","affiliation":[{"name":"Dana Farber Cancer Institute, Boston, Massachusetts. 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3341-9903","authenticated-orcid":false,"given":"J. 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