Emerging molecular targets and therapy for cholangiocarcinoma

Table 1 Mutation frequency for intrahepatic and extrahepatic cholangiocarcinoma

Genetic mutation	Frequency (%) in all tumours tested		Ref.
	Intrahepatic CC	Extrahepatic CC
IDH 1/2	14%-36%	0%	[27,59,67,99-101]
BAP 1	9%-25%	4%-10%	[66,67,101]
KRAS	9%-24%	40%-47%	[62-64,96]
TP53	3%-38%	18%-45%	[62-64,96]
PBRM1	11%-17%	4%-11%	[63,97]
ARID1A	11%-36%	5%-16%	[62-64,95]
EGFR amplification	7%	0%	[101]
HER2	0%-2%	0%-20%	[67,101]
VEGF overexpression	42%	31%	[46,47]
PIK3CA	4%-6%	9%	[66,101]
BRAF	4%-22%	6%	[57,101-103]
FRGR translocation	6%-50%	0%-5%	[66]
MCL1 amplification	16%-21%	NR	[66]
PTEN	1%-11%	4%	[59,101]
FBXW7	1%-6%	4%-15%	[67]
CDK6	7%	NR	[66]
CDKN2A	7%	15%	[66]
BRCA 1/2	4%	NR	[66]
SMAD4	1%-4%	11%-25%	[59,67,101]
mTOR	26%	40%	[67]

HER2: Human epidermal growth factor 2; CC: Cholangiocarcinoma; NR: No report.

Table 2 Clinical trials of novel agents in cholangiocarcinoma

Title	Target	Phase	Estimated sample size	Expected completion date	Trial number
CX-4945 in combination with gemcitabine and cisplatin for frontline treatment of CCA	Casein kinase 2	I/II	100	Dec 2016	NCT02128282
BGJ398 in patients with advanced CCA and FGFR gene fusion	FGFR gene fusion	II	55	Jul 2018	NCT02150967
Dasatanib in IDH-mutant advanced ICC		II	19	Sep 2022	NCT02428855
RRx-001 in second line treatment of advanced CCA prior to readministration of first line therapy	Epigenetic modifications	II	30	May 2018	NCT02452970
ASLAN001 in advanced CCA who progressed on at least 1 line of therapy	Pan-HER inhibitor	II	25	Dec 2017	NCT02609958
Regorafanib as single agent in advanced CCA who failed first line	Multi-kinase inhibitor (VEGF, KIT, PDGF, FGFR, BRAF)	II	37	Feb 2018	NCT02053376
Copanlisib in combination with gemcitabine and cisplatin in advanced CCA	PI3K inhibitor	II	25	Dec 2018	NCT02631590
LDK378 in ROS1/ALK overexpressed advanced CCA	ROS1 and/or ALK	II	34	Jul 2018	NCT02374489
AG120 in advanced solid tumours with IDH1 mutation	IDH1	I	145	May 2016	NCT02073994
Study of LY2801653 in advanced cancer	MET inhibitor	I	190	Nov 2017	NCT01285037
ABC-08: Acelarin in combination with cisplatin in locally advanced/metastatic biliary tract cancers	Nucleotide analogue	I	24	Sep 2018	NCT02352765
Ramucirumab for advanced pre-treated biliary cancers	VEGFR2 antagonist	II	50	Dec 2019	NCT02520141
Keynote-158: Pembrolizumab in participants with advanced solid tumours	PD1 inhibitor	II	1100	Mar 2021	NCT02628067
Immunotherapy using TILs for patients with metastatic cancer	Adoptive T-cell therapy	II	33	Dec 2019	NCT01174121

CCA: Cholangiocarcinoma; EGFR: Epidermal growth factor receptor; FGFR: Fibroblast growth factor receptor; IDH: Isocitrate dehydrogenase; PD1: Programmed death 1; TIL: Tumour infiltrating lymphocytes; VEGF: Vascular endothelial growth factor.

Table 3 Fibroblast growth factor receptor fusions according to reported frequency in cholangiocarcinoma

FGFR fusion partner	Frequency	Ref.
FGFR2-AHCYL	7/102 (7%)	[56]
FGFR2-BICC1	2/102 (2%)	[56]
	41/107 (38%)	[57]
	1/28 (4%)	[66]
FGFR2-PPHLN1	17/107 (16%)	[57]
FGFR2-MGEA5	1/6 (17%)	[62]
FGFR2-TACC3	1/6 (17%)	[62]
	1/28 (4%)	[66]
FGFR-KIAA1598	1/28 (4%)	[66]

FGFR: Fibroblast growth factor receptor.