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
  • 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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