Futibatinib, an investigational agent for the treatment of intrahepatic cholangiocarcinoma: evidence to date and future perspectives

Figures & data

Box 1. Drug Summary

Drug name	Futibatinib (TAS-120)
Class	Antineoplastics; Ketones; Pyrazoles; Pyrimidines; Pyrrolidines; Small molecules
Molecular formula	C22H22N6O3
PubChem CID	71,621,331
Phase	Futibatinib is being evaluated in phase 1 and phase 2 for iCCAs harboring FGFR2 fusions. A phase 3 trial, the FOENIX-CCA3 study (NCT04093362) comparing futibatinib versus cisplatin plus gemcitabine as first-line treatment is currently ongoing.
Targets	FGFR1, FGFR2, FGFR3, FGFR4
Most frequent adverse events	hyperphosphatemia, diarrhea, dry mouth
Route of administration	20 mg orally once-daily, continuously (21-day cycles)
Pivotal trials	interim analysis of FOENIX-CCA2 trial evaluating futibatinib as second or further line of treatment in iCCA patients harboring FGFR2 gene fusions or other rearrangements has been presented at the 2020 ASCO Annual Meeting.

Table 1. Properties and names of small molecule FGFR family inhibitors. FGFR: Fibroblast Growth Factor Receptor; VEGFR: Vascular Endothelial Growth Factor Receptor; PDGFR: Platelet-Derived Growth Factor Receptor; RET: Rearranged during Transfection

Name	Inhibitory FGFR action	Targets	Formula
Erdafitinib	Reversible inhibitor with drug-FGFR X-ray crystal structure	FGFR1, FGFR2, FGFR3, FGFR4, VEGFR2	C25H30N6O2
Ponatinib	Reversible inhibitor with drug-FGFR X-ray crystal structure	FGFR1, FGFR2, FGFR3, FGFR4, VEGFR1, VEGFR2, VEGFR3, Abl, PDGFα, PDGFβ, RET, Kit, CSF1R, Flt3	C29H27F3N6O
Dovitinib	Reversible inhibitor with drug-FGFR X-ray crystal structure	FGFR1, FGFR3, VEGFR1, VEGFR2, VEFGR3, PDGFRβ, RET, Kit	C21H21FN6O
AZD4547	Reversible inhibitor with drug-FGFR X-ray crystal structure	FGFR1, FGFR2, FGFR3, VEGFR2, CSF1R, Kit	C26H33N5O3
Debio 1347	Reversible inhibitor with drug-FGFR X-ray crystal structure	FGFR1, FGFR2, FGFR3	C20H16N6O
Infigratinib (BJG398)	Reversible inhibitor with drug-FGFR X-ray crystal structure	FGFR1, FGFR2, FGFR3	C26H31Cl2N7O3
Lenvatinib	Reversible inhibitor with drug-FGFR X-ray crystal structure	FGFR1, FGFR2, FGFR3, VEGFR1, VEGFR2, VEGFR3, RET, Kit	C21H19N4ClO4
Lucitanib	Reversible inhibitor with drug-FGFR X-ray crystal structure	FGFR1, VEGFR1, VEGFR2, PDGFRα, Src	C26H25N3O4
Futibatinib (TAS-120)	Irreversible inhibitor with drug-FGFR X-ray crystal structure	FGFR1, FGFR2, FGFR3, FGFR4	C22H22N6O3
Roblitinib (FGF401)	Irreversible inhibitor with drug-FGFR X-ray crystal structure	FGFR4	C25H30N8O4
Nintedanib (BIBF-1120)	Inhibitor without drug-FGFR X-ray crystal structure	FGFR1, VEGFR2, VEGFR3, PDGFRα	C31H33N5O4
Pazopanib (GW786034)	Inhibitor without drug-FGFR X-ray crystal structure	FGFR1, VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit	C21H23N7O2S
Pemigatinib (INCB054828)	Inhibitor without drug-FGFR X-ray crystal structure	FGFR1, FGFR2, FGFR3, FGFR4	C24H27F2N5O4
Rogaratinib	Inhibitor without drug-FGFR X-ray crystal structure	FGFR1, FGFR2, FGFR3, FGFR4	C23H26N6O3S
Fisogatinib (BLU-554)	Inhibitor without drug-FGFR X-ray crystal structure	FGFR4	C24H24Cl2N4O4

Figure 1. Fibroblast Growth Factor Receptor (FGFR) structure, ligand binding and signaling

FGFR structure includes two receptor molecules, two FGFs and HSPG (heparan sulfate proteoglycan) chain. FGF, HSPG, and FGFR constitute a complex, with subsequent transphosphorylation of tyrosine kinase domains. FRS acts as a key adaptor protein associated with GRB2, with activation of MAPK and PI3K/AKT signaling pathways.

Figure 2. Structural formula of futibatinib (TAS-120)

Figure 3. Structure of covalent Futibatinib-FGFR1complex. Futibatinib forms a covalent adduct with C488 while the oxygen atom of a methoxy group forms a hydrogen bond with the backbone NeH group of DFG-D641