2. Academic Validation
  3. RLY-4008, the First Highly Selective FGFR2 Inhibitor with Activity across FGFR2 Alterations and Resistance Mutations

RLY-4008, the First Highly Selective FGFR2 Inhibitor with Activity across FGFR2 Alterations and Resistance Mutations

  • Cancer Discov. 2023 Sep 6;13(9):2012-2031. doi: 10.1158/2159-8290.CD-23-0475.
Vivek Subbiah # 1,  Vaibhav Sahai # 2,  Dejan Maglic 3,  Kamil Bruderek 3,  B Barry Touré # 3,  Songping Zhao 3,  Roberto Valverde 3,  Patrick J O'Hearn 3,  Demetri T Moustakas 3,  Heike Schönherr 3,  Nastaran Gerami-Moayed 3,  Alexander M Taylor 3,  Brandi M Hudson # 3,  Damian J Houde 3,  Debjani Pal 3,  Lindsey Foster 3,  Hakan Gunaydin 3,  Pelin Ayaz 4,  Dina A Sharon # 4,  Lipika Goyal # 5,  Alison M Schram 6,  Suneel Kamath 7,  Cori Ann Sherwin 3,  Oleg Schmidt-Kittler 3,  Kai Yu Jen 3,  Fabien Ricard 3,  Beni B Wolf 3,  David E Shaw 4 8,  Donald A Bergstrom 3,  James Watters 3,  Jessica B Casaletto 3
Affiliations

Affiliations

  • 1 The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 2 University of Michigan, Ann Arbor, Michigan.
  • 3 Relay Therapeutics, Inc., Cambridge, Massachusetts.
  • 4 D. E. Shaw Research, New York, New York.
  • 5 Massachusetts General Hospital, Boston, Massachusetts.
  • 6 Memorial Sloan Kettering Cancer Center, New York, New York.
  • 7 The Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio.
  • 8 Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York.
  • # Contributed equally.
PMID: 37270847 DOI: 10.1158/2159-8290.CD-23-0475
Abstract

Oncogenic activation of Fibroblast Growth Factor receptor 2 (FGFR2) drives multiple cancers and represents a broad therapeutic opportunity, yet selective targeting of FGFR2 has not been achieved. Although the clinical efficacy of pan-FGFR inhibitors (pan-FGFRi) validates FGFR2 driver status in FGFR2 fusion-positive intrahepatic cholangiocarcinoma, their benefit is limited by incomplete target coverage due to FGFR1- and FGFR4-mediated toxicities (hyperphosphatemia and diarrhea, respectively) and the emergence of FGFR2 resistance mutations. RLY-4008 is a highly selective, irreversible FGFR2 Inhibitor designed to overcome these limitations. In vitro, RLY-4008 demonstrates >250- and >5,000-fold selectivity over FGFR1 and FGFR4, respectively, and targets primary alterations and resistance mutations. In vivo, RLY-4008 induces regression in multiple xenograft models-including models with FGFR2 resistance mutations that drive clinical progression on current pan-FGFRi-while sparing FGFR1 and FGFR4. In early clinical testing, RLY-4008 induced responses without clinically significant off-isoform FGFR toxicities, confirming the broad therapeutic potential of selective FGFR2 targeting.

Significance: Patients with FGFR2-driven cancers derive limited benefit from pan-FGFRi due to multiple FGFR1-4-mediated toxicities and acquired FGFR2 resistance mutations. RLY-4008 is a highly selective FGFR2 Inhibitor that targets primary alterations and resistance mutations and induces tumor regression while sparing other FGFRs, suggesting it may have broad therapeutic potential. See related commentary by Tripathi et al., p. 1964. This article is featured in Selected Articles from This Issue, p. 1949.

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