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

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

  • Cancer Discov. 2024 Sep 4;14(9):1599-1611. doi: 10.1158/2159-8290.CD-24-0024.
Rona Yaeger 1,  Meredith A McKean 2,  Rizwan Haq 3,  J Thaddeus Beck 4,  Matthew H Taylor 5,  Jonathan E Cohen 6,  Daniel W Bowles 7,  Shirish M Gadgeel 8,  Catalin Mihalcioiu 9,  Kyriakos P Papadopoulos 10,  Eli L Diamond 1,  Keren B Sturtz 11,  Gang Feng 12,  Stefanie K Drescher 11,  Micaela B Reddy 11,  Bhaswati Sengupta 11,  Arnab K Maity 12,  Suzy A Brown 11,  Anurag Singh 11,  Eric N Brown 11,  Brian R Baer 11,  Jim Wong 11,  Tung-Chung Mou 11,  Wen-I Wu 11,  Dean R Kahn 11,  Sunyana Gadal 1,  Neal Rosen 1,  John J Gaudino 11,  Patrice A Lee 11,  Dylan P Hartley 11,  S Michael Rothenberg 11 13
Affiliations

Affiliations

  • 1 Memorial Sloan Kettering Cancer Center, New York, New York.
  • 2 Sarah Cannon Research Institute, Nashville, Tennessee.
  • 3 Dana Farber Cancer Institute, Boston, Massachusetts.
  • 4 Highlands Oncology, Fayetteville, Arkansas.
  • 5 Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon.
  • 6 Hadassah Medical Center, Jerusalem, Israel.
  • 7 University of Colorado Hospital, Aurora, Colorado.
  • 8 Henry Ford Health System, Detroit, Michigan.
  • 9 McGill University Health Centre, Montreal, Canada.
  • 10 South Texas Accelerated Research Therapeutics, San Antonio, Texas.
  • 11 Pfizer Boulder Research and Development, Boulder, Colorado.
  • 12 Pfizer Early Clinical Development, Cambridge, Massachusetts.
  • 13 Pfizer Oncology Research and Development, La Jolla, California.
PMID: 38691346 DOI: 10.1158/2159-8290.CD-24-0024
Abstract

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.

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