Oncology Pipeline

Fibroblast growth factor (FGF) receptor 3 (FGFR3) is a member of the highly conserved FGFR family of transmembrane receptors.^2-5 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.^3,4,6-9 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.^2-5,10 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.¹¹

LOXO-435 is a highly potent and isoform-selective FGFR3 inhibitor that has shown significant antitumor activity across FGFR3-mutant in vivo preclinical models, with preserved potency against FGFR3 gatekeeper resistance mutants.⁹ LOXO-435 spares FGFR1 and FGFR2 in preclinical in vivo models, thus potentially avoiding dose-limiting hyperphosphatemia and other clinical adverse events that drive chronic intolerance to pan-FGFR inhibitors.⁹