Article
作者: Gadgeel, Shirish M. ; Taylor, Matthew H. ; Rothenberg, S. Michael ; Mou, Tung-Chung ; McKean, Meredith A. ; Brown, Suzy A. ; Gaudino, John J. ; Lee, Patrice A. ; Maity, Arnab K. ; Kahn, Dean R. ; Wu, Wen-I ; Wong, Jim ; Bowles, Daniel W. ; Drescher, Stefanie K. ; Hartley, Dylan P. ; Reddy, Micaela B. ; Sturtz, Keren B. ; Singh, Anurag ; Sengupta, Bhaswati ; Mihalcioiu, Catalin ; Papadopoulos, Kyriakos P. ; Brown, Eric N. ; Feng, Gang ; Diamond, Eli L. ; Haq, Rizwan ; Rosen, Neal ; Gadal, Sunyana ; Beck, J. Thaddeus ; Baer, Brian R. ; Yaeger, Rona ; Cohen, Jonathan E.
AbstractRAF inhibitors have transformed treatment for patients with BRAFV600-mutant cancers, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAFV600 dimerization, and poor brain penetration. 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 ± 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 ± 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.Significance: 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.