Biliary tract cancers: current knowledge, clinical candidates and future challenges

Figures & data

Figure 1 Anatomical sub-variants of BTC.

Abbreviations: AVC, ampulla of Vater cancer; BTC, biliary tract cancer; EHC, extrahepatic cholangiocarcinoma; GBC, gallbladder cancer; IHC, intrahepatic cholangiocarcinoma.

Figure 2 Important signaling pathways of potential therapeutic significance in patients with BTC.

Abbreviations: AKT/PKB, protein kinase B; ARID1A, AT-rich interactive domain containing protein 1A; BAP1, BRCA1-associated protein 1; BRAF, V-Raf murine sarcoma viral oncogene homolog B; BTC, biliary tract cancer; Dvl, disheveled protein; ErbB1, erythroblastic leukemia viral oncogene 1; ErbB2, erythroblastic leukemia viral oncogene 2; FGFR, fibroblast growth factor receptor; FZD, frizzled family; HDAC, histone deacetylase; IDH, isocitrate dehydrogenase; KRAS, Kirsten rat sarcoma viral oncogene homolog; MAPK/ERK pathway, mitogen-activated protein kinase/extracellular signal-regulated kinase pathway; mTOR, mammalian target of rapamycin; NADP, nicotinamide adenine dinucleotide phosphate; NADPH (reduced), nicotinamide adenine dinucleotide phosphate; PDGFR, plasma-derived growth factor receptor; PI3KCA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit A; PKA, protein kinase; PORC, serine O-palmitoyltransferase porcupine protein; PTEN, phosphatase and tensin homolog; RNF43, ubiquitin E3 ligase ring finger 43; TCF, T cell factor; VEGFR, vascular endothelial growth factor receptor; Wnt, Wingless-related integration; ZNRF3, E3 ubiquitin ligase zinc and ring finger 3.

Table 1 Association of survival and frequency of KRAS mutations in patients with BTC

References	Number of patients	Patient group	Frequency of KRAS mutations (%)	Impact on survival	P-value	OS in months in KRAS mutant type	OS in months in KRAS wt	Comments
35	111	EHC, GBC, AVC	41%	Worse OS	0.003	NA	NA	HR=2.94
36	86	IHC	22%	Worse OS	0.002	5.7	19.0
37	39	GBC	41%	Worse OS	0.003	12.5	17.0
26	75	CCA	24% in IHC	Worse OS	0.002	7.4	40.2
27	412	IHC, EHC, GBC	22% in IHC 42% in EHC 0% in GBC	Worse OS	0.04	38.2	49.2
38	80	AVC	35%	Worse OS	0.021	78	138

Abbreviations: AVC, ampulla of Vater cancer; BTC, biliary tract cancer; CCA, cholangiocarcinoma; EHC, extrahepatic cholangiocarcinoma; GBC, gallbladder cancer; IHC, intrahepatic cholangiocarcinoma; KRAS, Kirsten rat sarcoma viral oncogene homolog; NA, not available; OS, overall survival; wt, wild type.

Table 2 Frequency of FGF mutations across various anatomical subtypes of BTC and their association with survival

References	Number of patients	Patient groups	Frequency of FGFR mutations/fusions (%)	Association with survival	Comments
61	41	IHC, GBC	13% in IHC	NA	FGFR2 mutations
58	4	MBC, MPC, CCA	100% in CCA	NA	In 2/2 patients of CCA
62	28	IHC	14%	NA	Three gene fusions identified
60	156	IHC, EHC, intraductal papillary BTC	8%	FGFR2 translocation OS =123 months vs no translocation OS =37 months	Most mutations in IHC =13% All FGFR2 translocations OS P-value=0.039
56	102	CCA	13.6%	NA	No difference in OS noted
59	319	Lung, breast, papillary thyroid, glioblastoma, CCA	NA	NA	Presence of FGFR fusion in CCA sample
26	75	IHC, EHC	13% in IHC 5% in EHC	Better outcome	Indolent course of disease in carriers
27	412	IHC, EHC, GBC	11% in IHC 3% in GBC	Better outcome	P=0.001

Abbreviations: BTC, biliary tract cancer; CCA, cholangiocarcinoma; EHC, extrahepatic cholangiocarcinoma; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; GBC, gallbladder cancer; IHC, intrahepatic cholangiocarcinoma; MBC, metastatic breast cancer; MPC, metastatic prostate cancer; NA, not available; OS, overall survival.

Table 3 Association of survival and frequency of IDH mutations in patients with BTC

References	Methods	Number of patients	Patient group	Frequency of IDH mutations (%)	Impact on survival	P-value	OS in IDH mutant type	OS in IDH wt	Comments
61	Exome sequencing	41	IHC, GBC	19% in IHC	Worse OS	0.0034	33% 3-year survival	81% 3-year survival	Exclusive to IHC
27	Comprehensive genomic profiling	554	IHC, EHC, GBC	20% in IHC	Unable to show				Exclusive to IHC and 0% in EHC and GBC
143	Tumor mutational analysis	104	IHC	28.8%	Unable to report
144	Whole exome sequencing	326	IHC	7.5% in Chinese 25% in Caucasian	Worse relapse-free survival		45.3% 7-year relapse- free survival	81.3% 7-year relapse- free survival	Difference in frequency in races
142	Next-generation sequencing	412	IHC, EHC, GBC	22% in IHC 42% in EHC 0% in GBC	Worse OS	0.04	38.2	49.2

Abbreviations: BTC, biliary tract cancer; EHC, extrahepatic cholangiocarcinoma; GBC, gallbladder cancer; IDH, isocitrate dehydrogenase; IHC, intrahepatic cholangiocarcinoma; OS, overall survival; wt, wild type.

Table 4 Potential treatments for targeting EGFR in patients with BTC

References	Phase	Agent investigated	Number of patients	Patient group	Survival	Comment
145	II	Erlotinib	42	aBTC	8% confirmed response rate	28% in the EGFR group were PF at 5.52 months
107	III	Erlotinib with GemOx	268	IHC, EHC, GBC, AVC	30% ORR in the erlotinib arm	No difference in OS
146	II	Cetuximab with GemCape	34	aBTC	Median PFS =7.89 months	Median OS =14.45 months
147	II	Cetuximab with GemOx	122	aBTC	Median PFS =6.7 months vs 4.1 months (P=0.05)	No significant benefit in OS, no relation to KRAS mutation
148	II	Cetuximab with GemOx	150	aBTC	PFS =6.1 months	Failed to reach PEP (improvement in PFS)
149	II	Panitumumab with GemOx	46	Unresectable KRAS wt BTC	Median PFS =8.3 months	Median OS =10.0 months
150	II	Panitumumab with CisGem	93	KRAS wt aBTC and aGBC	PFS at 6 months =73% (P=0.24)	Failed to reach PEP. OS =21.4 months (P=0.35)
151	II	Panitumumab with GemOx	31	KRAS wt aBTC	Median PFS =10.6 months	Median OS =20.3 months

Abbreviations: aBTC, advanced biliary tract cancer; aGBC, advanced gallbladder cancer; AVC, ampulla of Vater cancer; CisGem, cisplatin and gemcitabine chemotherapy; EHC, extrahepatic cholangiocarcinoma; GBC, gallbladder cancer; GemCape, gemcitabine and capecitabine; GemOx, gemcitabine and oxaliplatin; IHC, intrahepatic cholangiocarcinoma; KRAS, Kirsten rat sarcoma viral oncogene homolog; ORR, overall response rate; OS, overall survival; PEP, primary end point; PF, progression free; PFS, progression-free survival; wt, wild type.

Table 5 Current trials involving molecular treatments in BTC registered on clinicaltrials.gov

NCT; references	Study	Phase	Status	Recruiting countries	Comments
NCT03144856^Citation152	Apatinib as second-line treatment in aBTC	II	Recruiting	China	VEGFR2 TKI
NCT02579616^Citation153	Lenvatinib (E7080) in unresectable BTC who have failed Gem-based combination	II	Active, not recruiting	Japan	VEGFR1/2/3 TKI
NCT02773459^Citation154	To test the efficacy of MEK162 with Cape in Gem-pretreated aBTC, predict biomarkers	I/II	Recruiting	Korea	MEK inhibitor
NCT03093870^Citation155	Multicentre double-blind, placebo-controlled study of varlitinib plus capecitabine vs placebo plus capecitabine in aBTC or mBTC as second-line treatment	II/III	Not yet recruiting	USA	EGFR, HER2, HER4 inhibitor
NCT03129074^Citation156	Varlitinib and Cape in aBTC and mBTC patients	II	Not yet recruiting	NA	EGFR, HER2, HER4 inhibitor
NCT03110484^Citation157	Pemetrexed with erlotinib as salvage treatment in mBTC patients who have failed Gem	II	Not yet recruiting	Korea	EGFR TKI
NCT02992340^Citation158	Varlitinib with GC for treatment-naïve aBTC or mBTC	I/II	Recruiting	Korea, Singapore, Taiwan	EGFR, HER2, HER4 inhibitor
NCT02711553^Citation159	Ramucirumab or merestinib or placebo with GC in aBTC or mBTC	II	Recruiting	Multinational	Ramucirumab = VEGFR2 antibody Merestinib = MET inhibitor
NCT02966821^Citation160	Sulfatinib as second-line treatment in patients with BTC	II	Recruiting	China	VEGFR and FGFR1 TKI
NCT02520141^Citation161	Ramucirumab for pretreated aBTC	II	Recruiting	USA	VEGFR2 antibody
NCT02836847^Citation162	Molecularly targeted therapy with GemOx in aEHC or rEHC and GBC	II	Recruiting	China	Precision target therapy
NCT02443324^Citation163	Ramucirumab with pembrolizumab in gastric, GEJ adenoca, NSCLC, TCC in urothelium or BTC	I	Recruiting	Multinational	Ramucirumab = VEGFR2 antibody Pembrolizumab = PD-1 antibody
NCT02386397^Citation164	Regorafenib dose for Phase II trial in combination with mGemOx in aBTC	I/II	Recruiting	France	Dual VEGFR-TIE2 TKI
NCT01825603^Citation165	ADH-1 with GC in patients with irresectable BTC/pancreatic ca	I	Recruiting	USA	Alcohol dehydrogenase 1 blocks N-cadherin
NCT03082053^Citation166	Varlitinib in Japanese subjects with advanced or MET solid tumors	I	Recruiting	Japan	EGFR, HER2, HER4 inhibitor
NCT00948935^Citation167	Panitumumab with GemIr in aBTC and mBTC	II	Ongoing but not recruiting	USA	EGFR antibody
NCT02151084^Citation48	Different dosing schedules of selumetinib with GC vs GC alone in BTC	II	Recruiting	Canada	MEK inhibitor
NCT02265341^Citation168	Ponatinib in aBTC patients with FGFR2 fusions	II	Recruiting	US	BCR–ABL inhibitor
NCT02451553^Citation169	Afatinib with Cape in advanced refractory solid tumors, pancreatic ca, BTC	I	Recruiting	USA	EGFR TKI
NCT02943031^Citation170	Effect of individualized precision therapy programs in patients with BTC	IV	Not yet recruiting	China	Precision therapy
NCT03185988^Citation171	Patients with metastatic disease of the digestive system	II	Not yet recruiting	China	Anti-HER2 therapy
NCT02042443^Citation172	Trametinib or combination chemotherapy in patients with refractory or advanced BTC or GBC that is irresectable	II	Active, not recruiting	USA	MEK inhibitor
NCT02586987^Citation173	Study to assess the safety and tolerability of ascending doses of selumetinib with MEDI4736 and selumetinib, MEDI4736, tremelimumab in advanced solid tumors	I	Recruiting	Multinational	Selumetinib = MEK inhibitor MEDI4736 = PD-L1 antibody Tremelimumab = CTLA4 antibody
NCT02128282^Citation174	CX-4945 in combination with GC as frontline treatment for CCA	I/II	Recruiting	Multinational	CK2 protein kinase inhibitor
NCT02053376^Citation175	Phase II trial of regorafenib in aBTC and mBTC, CCA patients who have failed first-line chemotherapy	II	Recruiting	USA	Dual VEGFR-TIE2 TKI
NCT02715089^Citation176	Precise treatment in hepatobiliary cancers	Observa- tional	Recruiting	China	Precision treatment
NCT01752920^Citation177	Phase I/II study of ARQ087 in advanced solid tumors with FGFR genetic alterations	I/II	Active, not recruiting	USA	Pan-FGFR inhibitor
NCT01855724^Citation178	Clinical trial to investigate the efficacy of treatment with Gem and pazopanib in BTC	II	Recruiting	Greece	C-KIT, FGFR, PDGFR and VEGFR inhibitor
NCT02631590^Citation179	Copanlisib with GC in aCCA	II	Recruiting	USA	PI3K inhibitor
NCT02576431^Citation180	Study of LOXO-101 (larotrectinib) in subjects with NTRK fusion-positive solid tumors (NAVIGATE)	II	Recruiting	Multinational	Tropomyosin receptor kinase inhibitor
NCT03027284^Citation181	Merestinib in Japanese patients with advanced or metastatic ca	I	Recruiting	Japan	MET inhibitor
NCT01766219^Citation182	CPI-613 in irresectable, advanced or metastatic BTC	I/II	Recruiting	USA	PDH and αKGDH inhibitor
NCT02495896^Citation183	Recombinant EphB4-HSA fusion protein with standard chemo in advanced or metastatic solid tumors	I	Recruiting	USA	Recombinant fusion protein composed of full length extracellular domain soluble of human receptor TK ephrin type B receptor 4
NCT03639935^Citation91	Rucaparib in combination with nivolumab in patients with advanced or mBTC following platinum	II	Not yet recruiting	USA	PARP inhibitor and PD-1 antibody
NCT02433639^Citation184	Study of TH-302 monotherapy as second-line treatment in aBTC	II	Unknown	South Korea	Hypoxia activated prodrug
NCT03185988^Citation185	Anti-HER2 therapy in patients with metastatic disease and HER2-positive disease of the digestive system	II	Not yet recruiting	China	HER2 antibody
NCT02115542^Citation186	Single-agent regorafenib in refractory aBTC	II	Active	USA	Multikinase inhibitor
NCT03093870^Citation187	Varlitinib in combination with capecitabine for metastatic and aBTC	II/III	Recruiting	Multinational	HER inhibitor
NCT03337087^Citation91	Liposomal irinotecan, fluorouracil, leucovorin calcium and rucaparib in treating patients with metastatic pancreatic, colorectal, gastroesophageal or BTC	I/II	Not yet recruiting	USA	PARP inhibitor
NCT02715089^Citation188	Precise treatment in hepatobiliary cancers		Recruiting	China	Use of NGS to obtain genomic data and targeting specific mutations with precision medicines
NCT02631590^Citation189	Copanlisib (BAY 80-6946) in combination with GC in aCCA	II	Recruiting	USA	PI3K inhibitor
NCT03230318^Citation177	ARQ087 in subjects with FGFR2 gene fusion- positive inoperable or advanced IHC	II	Recruiting	USA, Canada and Italy	Pan-FGFR inhibitor

Abbreviations: aBTC, advanced biliary tract cancer; aCCA, advanced cholangiocarcinoma; αKGDH, α-ketoglutarate dehydrogenase; BTC, biliary tract cancer; Bcr-abl, bcr-abl fusion oncogene/Philadelphia chromosome; ca, carcinoma; chemo, chemotherapy; CCA, cholangiocarcinoma; cKIT, proto-oncogene c-Kit; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; FGFR, fibroblast growth factor receptor; GEJ, gastro-esophageal junction; GBC, gallbladder cancer; GC, gemcitabine and cisplatin; gem, gemcitabine; GemCape, gemcitabine and capecitabine; GemOx, gemcitabine and oxaliplatin; HCC, hepatocellular carcinoma; HER, human EGF receptor; HER2, human EGF receptor 2; IHC, intrahepatic cholangiocarcinoma; mBTC, metastatic biliary tract cancer; MEK, mitogen-activated protein kinase; MET, MET proto-oncogene, mesenchymal to epithelial transition proto-oncogene; NGS, next generation sequencing; ; NA, not available; NSCLC, non-small-cell lung cancer; PARP, poly-ADP ribose polymerase; PD-1, programmed death 1; PDGFR, plasma-derived growth factor receptor; PDH, pyruvate dehydrogenase; PD-L1, programmed cell death ligand-1; PI3K, phosphoinositide 3-kinase; TIE2, TCC, transitional cell carcinoma; TIE family of angiopoietin receptor kinase; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Table 6 Current trials involving the immune system in BTC registered on clinicaltrials.gov

NCT	Study	Phase	Status	Recruiting countries	Comment
NCT02829918^Citation190	Nivolumab in patients with aBTC which is refractory	II	Recruiting	USA	PD-1 antibody
NCT03110328^Citation191	Pembrolizumab in mBTC as second-line treatment after failing one cytotoxic chemo	II	Not yet open	Korea	PD-1 antibody
NCT03046862^Citation192	Durvalumab/tremelimumab in combination with GC in chemo-naïve BTC patients	II	Recruiting	Korea	Durvalumab = PD-L1 antibody Tremelimumab = CTLA-4 antibody
NCT03101566^Citation193	Nivolumab in combination with GC or ipilimumab in aBTC	II	Not yet open	USA	Nivolumab = PD-1 antibody Ipilimumab = CTLA4 antibody
NCT02632019^Citation194	Immunotherapy using precision T cells specific to neo-antigens for the treatment of advanced BTC	I/II	Recruiting	China	Dendritic cell precision T cells against neoantigen
NCT02586987^Citation173	Study to assess the safety and tolerability of ascending doses of selumetinib with MEDI4736 and selumetinib, MEDI4736, tremelimumab in advanced solid tumors	I	Recruiting	Multinational	Selumetinib = MEK inhibitor MEDI4736= PD-L1 antibody Tremelimumab = CTLA4 antibody
NCT01938612^Citation195	Phase I, open-label, multicentre study to evaluate MEDI4736 in advanced solid tumors	I	Recruiting	Multinational	PD-L1 antibody
NCT02628067^Citation196	Pembrolizumab in patients with advanced solid tumors, KEYNOTE-158	II	Recruiting	Multinational	PD-1 antibody
NCT02821754^Citation197	Pilot study of combined immune check point inhibitors with ablative therapy in HCC and BTC	I/II	Recruiting	USA	Durvalumab = PD-L1 antibody Tremelimumab = CTLA4 antibody
NCT01853618^Citation198	Tremelimumab with chemoembolization or ablation for liver ca	I	Active, not recruiting	USA	CTLA4 antibody
NCT02662348^Citation199	T cell-mediated adaptive therapy for Her2- positive digestive system ca	I	Enrolling by invitation	China	HER2 Bi-armed T cells
NCT03482102^Citation200	Durvalumab (MEDI4736) and tremelimumab and radiation therapy in HCC and BTC	II	Recruiting	USA	PD-L1 antibody and anti- CTLA4
NCT03111732^Citation201	Pembrolizumab with CapeOx in aBTC	II	Recruiting	USA	PD-1 antibody
NCT03260712^Citation202	Pembrolizumab in BTC	II	Not yet recruiting	Germany	PD-1 antibody
NCT03358849^Citation203	Evaluation of the safety of allogeneic NKC (SMT-NK) cell therapy in aBTC	I	Recruiting	South Korea	Human NKC therapy designated as SMT 01

Notes: Tariq NU, Vogel A, McNamara MG, Valle JW. Biliary tract cancer: implicated immune-mediated pathways and their associated potential targets. Oncol Res Treat. 2018;41(5):298–304. Copyright © 2018 Karger Publishers, Basel, Switzerland.²⁰³

Abbreviations: aBTC, advanced biliary tract cancer; aCCA, advanced cholangiocarcinoma; BTC, biliary tract cancer; ca, carcinoma; CapeOx, capecitabine and oxaliplatin; CCA, cholangiocarcinoma; chemo, chemotherapy; CTLA4, cytotoxic T-lymphocyte-associated antigen 4; GBC, gallbladder cancer; GC, gemcitabine and cisplatin; HCC, hepatocellular carcinoma; HER, human EGF receptor; mBTC, metastatic biliary tract cancer; MEK, mitogen-activated protein kinase; NKC, natural killer cell; PD-1, programmed death 1; PD-L1, programmed cell death ligand-1; TKI, tyrosine kinase inhibitor.

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