2. Academic Validation
  3. Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations

Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations

  • Nat Cancer. 2023 Sep;4(9):1345-1361. doi: 10.1038/s43018-023-00630-y.
Isao Miyazaki # 1,  Igor Odintsov # 2 3 4,  Keiji Ishida 5,  Allan J W Lui 2 6,  Masanori Kato 5,  Tatsuya Suzuki 5,  Tom Zhang 2,  Kentaro Wakayama 5,  Renate I Kurth 2,  Ryan Cheng 2,  Hidenori Fujita 5,  Lukas Delasos 2 7,  Morana Vojnic 2 3 8,  Inna Khodos 9,  Yukari Yamada 5,  Kota Ishizawa 3 10,  Marissa S Mattar 2,  Kaoru Funabashi 5,  Qing Chang 9,  Shuichi Ohkubo 5,  Wakako Yano 5,  Ryuichiro Terada 5,  Claudio Giuliano 11,  Yue Christine Lu 2,  Annalisa Bonifacio 11,  Siddharth Kunte 2 12,  Monika A Davare 13,  Emily H Cheng 3,  Elisa de Stanchina 9,  Emanuela Lovati 11,  Yoshikazu Iwasawa 5,  Marc Ladanyi 2 3,  Romel Somwar 14 15
Affiliations

Affiliations

  • 1 Taiho Pharmaceutical Co. Ltd., Tsukuba, Japan. isao-miyazaki@taiho.co.jp.
  • 2 Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 3 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 4 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 5 Taiho Pharmaceutical Co. Ltd., Tsukuba, Japan.
  • 6 Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  • 7 Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA.
  • 8 Northwell Health Cancer Institute, Lenox Hill Hospital, New York, NY, USA.
  • 9 Antitumor Assessment Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 10 Department of Education and Support for Regional Medicine, Tohoku University Hospital, Sendai, Japan.
  • 11 Helsinn Healthcare SA, Lugano, Switzerland.
  • 12 Dana Cancer Center, Toledo, OH, USA.
  • 13 Department of Pediatrics, Oregon Health Sciences University, Portland, OR, USA.
  • 14 Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. somwarr@mskcc.org.
  • 15 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. somwarr@mskcc.org.
  • # Contributed equally.
PMID: 37743366 DOI: 10.1038/s43018-023-00630-y
Abstract

RET receptor tyrosine kinase is activated in various cancers (lung, thyroid, colon and pancreatic, among Others) through oncogenic fusions or gain-of-function single-nucleotide variants. Small-molecule RET kinase inhibitors became standard-of-care therapy for advanced malignancies driven by RET. The therapeutic benefit of RET inhibitors is limited, however, by acquired mutations in the drug target as well as brain metastasis, presumably due to inadequate brain penetration. Here, we perform preclinical characterization of vepafestinib (TAS0953/HM06), a next-generation RET Inhibitor with a unique binding mode. We demonstrate that vepafestinib has best-in-class selectivity against RET, while exerting activity against commonly reported on-target resistance mutations (variants in RETL730, RETV804 and RETG810), and shows superior pharmacokinetic properties in the brain when compared to currently approved RET drugs. We further show that these properties translate into improved tumor control in an intracranial model of RET-driven Cancer. Our results underscore the clinical potential of vepafestinib in treating RET-driven cancers.

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