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

Table 1 Search strategy summary

Items	Specification
Date of search	Jun 5, 2025
Databases and other sources searched	PubMed, EMBASE, Web of Science, Google Scholar and Cochrane Library
Search terms used	Hepatocellular carcinoma, fibroblast growth factor 19, fibroblast growth factor receptor 4, FGFR4 inhibitor, targeted therapy, multi-kinase inhibitor, immunotherapy, immune checkpoint inhibitor, biomarker
Timeframe	1990-2025
Inclusion criteria	(1) Study type: All types; and (2) Language: English
Selection process	The literature was independently screened by two professionals, and any discrepancies were resolved through discussion to achieve consensus

FGFR4: Fibroblast growth factor receptor 4.

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.

Table 3 Diagnostic performance of serum fibroblast growth factor 19 Levels and other existing markers alone and in combination for differentiation of hepatocellular carcinoma

Cut-off value of FGF19	Biomarker	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	AUC value
FGF19 cut-off value: 200 pg/mL[129]	FGF19 ≥ 200 pg/mL	53.2	95.1	95.9	48.7	0.795
	FGF19 ≥ 200 pg/mL and AFP ≥ 20 ng/mL	76.0	91.5	95.1	64.0
	FGF19 ≥ 200 pg/mL and DCP ≥ 40 mAU/mL	81.3	91.0	95.4	68.8
	FGF19 ≥ 200 pg/mL and AFP ≥ 20 ng/mL, DCP ≥ 40 mAU/mL	87.5	87.2	94.0	76.3
FGF19 cut-off value: 180 pg/mL[130]	FGF19 > 180 pg/mL	100	90	90	100	0.98
FGF19 cut-off value: 140.8 pg/mL[131]	FGF19 ≥ 140.8 pg/mL	81.8	87.9	87.1	82.9
	FGF19 ≥ 140.8 pg/mL and AFP ≥ 13.1 ng/mL	93.9	66.7	75.6	90.9
	FGF19 ≥ 140.8 pg/mL and DCP ≥ 0.725 ng/mL	90.9	45.5	62.5	83.3
	FGF19 ≥ 140.8 pg/mL and AFP ≥ 13.1 ng/mL, DCP ≥ 0.725 ng/mL	93.9	27.3	56.4	81.8

FGF19: Fibroblast growth factor-19; AFP: Alpha-fetoprotein; DCP: Des-γ-carboxy prothrombin; PPV: Positive predictive value; NPV: Negative predictive value; AUC: Area under the curve.