Fibroblast growth factor 19-fibroblast growth factor receptor 4 axis: From oncogenesis to targeted-immunotherapy in advanced hepatocellular carcinoma

Table 2 Clinical trial of selective fibroblast growth factor receptor 4 inhibitors

Drug	FGFR4 IC50	Participants	Key outcomes	Adverse events	ClinicalTrial.gov ID (phase)
H3B-6527[44]	< 1.2 nM	128	Part II H3B-6527 1000 mg QD	AEs (All)	NCT02834780 (I)
			ORR: 5.6% mOS: 9.5 months mPFS: 2.6 months	Diarrhea: 58.6% Nausea: 25% Fatigue: 20.3%
			Part II H3B-6527 500 mg BID	sAEs
			ORR: 0% mOS: 7.7 months mPFS: 3.0 months	Asthenia: 3.9% Tumor haemorrhage: 3.1%
Fisogatinib (BLU-554)[46]	3 nM	115	FGF19 IHC positive	AE (All grades): 96%	NCT02508467 (I)
			ORR: 17% DCR: 62% mPFS: 3.3 months	Diarrhea: 74% Nausea: 42% Vomitting: 35%
			FGF19 IHC negative	AE (grade ≥ 3): 43%
			ORR: 0% DCR: 50% mPFS: 2.3 months
Fisogatinib + CS1001[47]		26	Phase Ib	AEs (All)	NCT04194801 (Ib/II)
			Fisogatinib 400 mg + CS1001 1200 mg: ORR: 0% mOS: 16.2 months mPFS: 2.3 months	Blood bilirubin increased: 76.9%
			Fisogatinib 600 mg + CS1001 1200 mg	ALT increased: 76.9% AST increased: 76.9%
			ORR: 14.3% DCR: 42.9% mPFS: 2.1 months	sAEs
			Phase II	ALT increased: 7.7% AST increased: 7.7%
			Fisogatinib 600 mg + CS1001 1200 mg
			ORR: 20% DCR: 60% mPFS: 4.1 months
Roblitinib (FGF401)[52]	3 nM	160	Phase I	AEs (All)	NCT02325739 (I/II)
			ORR: 6.6% DCR: 59.0%	Diarrhea: 74.4% AST increased: 49.4% ALT increased: 45%
			Phase II	sAEs
			ORR: 6.1% DCR: 53%	Abdominal pain: 5.6% Ascites: 3.1% Haemoptysis: 2.5%
Roblitinib + PDR001[52]		12	FGF401 80 mg + PDR001 300 mg	AEs	NCT02325739 (I/II)
			ORR: 16.7% DCR: 50%	Diarrhea: 75% AST increased: 50% Hyperphosphataemia: 41.7%
			FGF401 120 mg + PDR001 300 mg	sAEs
			ORR: 16.7% DCR: 50%	Diarrhea: 16.7% Pyrexia: 16.7%
ABSK-011[53]	4.35 nM	75	CR: 1	AEs (All grades)	NCT04906434 (I)
			PR: 12	Diarrhea: 72.0% ALT increased: 70.7% AST increased: 57.3%
			BID dosing ORR: 43.5%	AEs (Grade ≥ 3)
				ALT increased: 10.7% AST increased: 9.3% Diarrhea: 5.3%
ABSK-011 + Atezolizumab[54]		36	PR: 7	AEs: 83.3%	NCT05441475 (II)
			DOR: 15.4 months	sAEs
			ABSK-011 220 mg BID + Atezolizumab 1200 mg IV Q3W: ORR: 55.6%	ALT increased: 8.3% AST increased: 5.6%; Blood bilirubin increased: 5.6% haematochezia: 2.8%

FGF19: Fibroblast growth factor 19; FGFR4: Fibroblast growth factor receptor 4; IHC: Immunohistochemistry; ORR: Objective response rate; DCR: Disease control rate; mPFS: Median progression-free survival; AE: Adverse events; sAE: Serious adverse events; mOS: Median overall survival; ALT: Alanine aminotransferase; AST: Aspartate transaminase; CR: Complete response; PR: Partial response; DOR: Duration of response; IV: Intravenous.