FGFR3 Inhibitor

LOXO-435

FGFR3_Inhibitor

Repetto M, et al1; Chen L, et al2

Target
Fibroblast growth factor (FGF) receptor 3 (FGFR3) is a member of the highly conserved FGFR family of transmembrane receptors.2-4 There are four FGF receptors, FGFR1-4, that each consist of an extracellular ligand-binding domain, transmembrane domain, and an intracellular tyrosine kinase domain.3,4 Receptor dimerization induced upon binding of the extracellular domain with a high-affinity member of the FGF family of ligands leads to phosphorylation of the intracellular domain and phospholipase Cγ, PI3K-AKT, RAS-MAPK-ERK, and STAT pathways activation, playing a critical role in several biological and developmental processes.2,4,5 FGFR3 aberrations act as oncogenes across tumor types and have been identified in 15% to 20% of advanced urothelial bladder cancers, ~15% of uterine carcinosarcomas, ~5% of endometrial cancers, and less frequently (<5%) in other solid tumor malignancies.3,4,6,7 Activating FGFR3 alterations are diverse and include point mutations, fusions, amplifications, and overexpression.2-5 Dysregulation of FGFR3 promotes oncogenesis and tumor cell proliferation, migration, and survival.2-5,8 Inhibition of oncogenic FGFR3 shows clinical benefit in patients with advanced urothelial cancer; however, currently approved FGFR targeted therapies that are not specific to FGFR3 demonstrate limited efficacy, dose-limiting off-target toxicities, and susceptibility to resistance mutations.7,9
Molecule
LOXO-435 is an isoform-selective FGFR3 inhibitor that has shown antitumor activity across FGFR3-mutant in vivo preclinical models, with preserved potency against FGFR3 gatekeeper resistance mutants.7 LOXO-435 spares FGFR1 and FGFR2 in preclinical in vivo models, with the goal of avoiding dose-limiting hyperphosphatemia and other clinical adverse events that drive chronic intolerance to pan-FGFR inhibitors.7
Clinical Development
LOXO-435 is being investigated in an open-label, multicenter, phase 1a/b study in patients with FGFR3-altered advanced urothelial carcinoma and other solid tumors.

References

  1. Repetto M, et al. Expert Rev Clin Pharmacol. 2021;14(10):1233-1252.
  2. Chen L, et al. J Exp Clin Cancer Res. 2021;40(1):345.
  3. Krook MA, et al. Br J Cancer. 2021;124(5):880-892.
  4. Katoh M. Nat Rev Clin Oncol. 2019;16(2):105-122.
  5. Glaser AP, et al. Nat Rev Urol. 2017;14(4):215-229.
  6. Helsten T, et al. Clin Cancer Res. 2016;22(1):259-267.
  7. Ballard JA, et al. Mol Cancer Ther. 2021;20(12_Suppl):P141.
  8. Haugsten EM, et al. Mol Cancer Res. 2010;8(11):1439-1452.
  9. Loriot Y, et al. N Engl J Med. 2019;381(4):338-348.
Clinical Development
LOXO-435 is being investigated in an open-label, multicenter, phase 1a/b study in patients with FGFR3-altered advanced urothelial carcinoma and other solid tumors.

References

  1. Repetto M, et al. Expert Rev Clin Pharmacol. 2021;14(10):1233-1252.
  2. Chen L, et al. J Exp Clin Cancer Res. 2021;40(1):345.
  3. Krook MA, et al. Br J Cancer. 2021;124(5):880-892.
  4. Katoh M. Nat Rev Clin Oncol. 2019;16(2):105-122.
  5. Glaser AP, et al. Nat Rev Urol. 2017;14(4):215-229.
  6. Helsten T, et al. Clin Cancer Res. 2016;22(1):259-267.
  7. Ballard JA, et al. Mol Cancer Ther. 2021;20(12_Suppl):P141.
  8. Haugsten EM, et al. Mol Cancer Res. 2010;8(11):1439-1452.
  9. Loriot Y, et al. N Engl J Med. 2019;381(4):338-348.

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The safety and efficacy of the agents under investigation have not been established. There is no guarantee that the agents will receive regulatory approval and become commercially available for the uses being investigated.

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