SUMMARY

• Erdafitinib is an orally bioavailable and selective pan-fibroblast growth factor receptor (FGFR 1, 2, 3, and 4) tyrosine kinase inhibitor.¹
• Fibroblast growth factor (FGF)/FGFR signaling is fundamentally involved in the normal physiologic processes.²
• Aberrant FGFR signaling is recognized to have an important role in the pathogenesis of cancer.²
• FGFR aberrations have been identified in a wide variety of tumor types, including urothelial carcinoma (UC).⁴
• Erdafitinib has inhibitory activity against FGFRs in vitro with 50% inhibitory concentration (IC₅₀) values in the low nanomolar range (1.2-5.7 nmol/L) for FGFR 1, 2, 3, and 4.¹
• Erdafitinib has also demonstrated binding to other kinases, including RET, CSF1R, PDGFRA, PDGFRB, FLT4, KIT, and VEGFR2.¹
• Erdafitinib causes prolonged inhibition of FGFR phosphorylation in vitro ranging from 8  to 72 hours, depending on the level of inhibition (complete vs partial).⁵
• Rapid uptake of erdafitinib into the lysosomal compartment of cells was demonstrated in vitro, which may contribute to prolonged inhibition of FGFR signaling.¹
• Erdafitinib demonstrated antitumor activity in a variety of cancer cell lines, including bladder cancer.¹

BACKGROUND

The FGF/FGFR signaling pathway is fundamentally involved in the normal physiologic processes, including embryogenesis, adult tissue homeostasis, tissue repair, wound healing, and inflammation, as identified in a literature review. The 4 FGFRs (FGFR1, FGFR2, FGFR3, and FGFR4) are transmembrane receptors with intracellular tyrosine kinase domains. Following FGF-ligand binding and FGFR dimerization, the intracellular kinase domains transphosphorylate, which leads to docking of adapter proteins and activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT pathways. The primary effects of the FGFR pathway include cell proliferation, migration, and antiapoptotic signals.²

Aberrant FGFR signaling is recognized to have an important role in the pathogenesis of cancer, and genomic alterations of FGFR can occur via ligand-independent and ligand-dependent mechanisms, as described in a literature review. Ligand-independent mechanisms include activating mutations, chromosomal translocations, and gene amplifications. Ligand-dependent mechanisms involve paracrine/autocrine signaling and angiogenesis.² A review of published literature described that aberrant FGF signaling can promote tumor development by directly driving cancer cell proliferation and survival and by supporting angiogenesis.³

FGFR aberrations have been identified in a wide variety of tumor types, including UC.⁴ FGFR3 mutations in UC occur more frequently in non-muscle-invasive disease than in muscle-invasive disease.^4,6,7

MECHANISM OF ACTION OF ERDAFITINIB

Erdafitinib is an orally bioavailable and selective pan-FGFR (1, 2, 3, and 4) tyrosine kinase inhibitor.¹

In Vitro Kinase Inhibitory Activity

In vitro assays demonstrated that erdafitinib has inhibitory activity against FGFRs, with all 4 FGFR family members being inhibited at the IC₅₀ values in the low nanomolar range (1.2-5.7 nmol/L) in time-resolved fluorescence assays as shown in Table: Inhibitory Activity Against FGFRs in Time-Resolved Fluorescence Assays.¹

Erdafitinib has also demonstrated binding to other kinases, including RET, CSF1R, PDGFRA, PDGFRB, FLT4, KIT, and VEGFR2.¹

FGFR Phosphorylation Inhibition

Inhibition of FGFR phosphorylation by the western blot test was evaluated in Kato III cells in vitro. Phospho-FGF receptor antibody testing showed that erdafitinib causes prolonged inhibition of FGFR phosphorylation. Complete inhibition of FGFR phosphorylation occurred for at least 8 hours post washout with partial inhibition of FGFR phosphorylation throughout the 72-hour observation period.⁵

Lysosomal Accumulation

Rapid uptake of erdafitinib into the lysosomal compartment of cells was demonstrated in vitro, which may contribute to prolonged inhibition of FGFR signaling.¹

Antitumor Activity

Erdafitinib demonstrated antitumor activity in a variety of cancer cell lines as shown in Table: Antitumor Activity in Multiple Cell Lines.¹

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and DerwentDrug Files (and/or other resources, including internal/external databases) was conducted on 10 October 2024.