A next-generation BRAF inhibitor overcomes resistance to BRAF inhibition in patients with BRAF-mutant cancers using pharmacokinetics-informed dose escalation
Recommended Citation
Yaeger R, McKean MA, Haq R, Beck JT, Taylor MH, Cohen JE, Bowles DW, Gadgeel SM, Mihalcioiu C, Papadopoulos KP, Diamond EL, Sturtz KB, Feng G, Drescher SK, Reddy MB, Sengupta B, Maity AK, Brown SA, Singh A, Brown EN, Baer BR, Wong J, Mou TC, Wu WI, Kahn DR, Gadal S, Rosen N, Gaudino JJ, Lee PA, Hartley DP, and Rothenberg SM. A next-generation BRAF inhibitor overcomes resistance to BRAF inhibition in patients with BRAF-mutant cancers using pharmacokinetics-informed dose escalation. Cancer Discov 2024.
Document Type
Article
Publication Date
4-30-2024
Publication Title
Cancer Discov
Abstract
RAF inhibitors have transformed treatment for BRAF V600-mutant cancer patients, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAF V600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by 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 ± binimetinib inhibited growth of mouse xenograft tumors driven by mutant BRAF that functions as dimers and by BRAF V600E 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 ± binimetinib was well-tolerated and resulted in multiple confirmed responses, systemically and in the brain, in BRAF-mutant cancer patients refractory to approved RAF inhibitors.
PubMed ID
38691346
ePublication
ePub ahead of print
