A Next-Generation BRAF Inhibitor Overcomes Resistance to BRAF Inhibition in Patients with BRAF-Mutant Cancers Using Pharmacokinetics-Informed Dose Escalation

• Published in: Cancer discovery Vol. 14; no. 9; p. 1599
• Main Authors: Yaeger, Rona, McKean, Meredith A, Haq, Rizwan, Beck, J Thaddeus, Taylor, Matthew H, Cohen, Jonathan E, Bowles, Daniel W, Gadgeel, Shirish M, Mihalcioiu, Catalin, Papadopoulos, Kyriakos P, Diamond, Eli L, Sturtz, Keren B, Feng, Gang, Drescher, Stefanie K, Reddy, Micaela B, Sengupta, Bhaswati, Maity, Arnab K, Brown, Suzy A, Singh, Anurag, Brown, Eric N, Baer, Brian R, Wong, Jim, Mou, Tung-Chung, Wu, Wen-I, Kahn, Dean R, Gadal, Sunyana, Rosen, Neal, Gaudino, John J, Lee, Patrice A, Hartley, Dylan P, Rothenberg, S Michael
• Format: Journal Article
• Language: English
• Published: United States 04-09-2024
• Subjects: Adult; Aged; Animals; Benzimidazoles - administration & dosage; Benzimidazoles - pharmacokinetics; Benzimidazoles - pharmacology; Benzimidazoles - therapeutic use; Cell Line, Tumor; Drug Resistance, Neoplasm - drug effects; Female; Humans; Male; Mice; Middle Aged; Mutation; Neoplasms - drug therapy; Neoplasms - genetics; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - genetics; Xenograft Model Antitumor Assays
• ISSN: 2159-8290
• DOI: 10.1158/2159-8290.CD-24-0024

RAF 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.