Biliary tract cancer management - now and future

Biliary tract cancer management - now and future: Comparison

Please note this is a comparison between Version 1 by Ashish Manne and Version 3 by Peter Tang.

Biliary tract cancers (BTC) comprise a group of malignancies originating in the epithelium of the biliary tract. These include cholangiocarcinoma (CCA) and gallbladder carcinoma (GBC). Intrahepatic cholangiocarcinoma or iCCA refers to tumors proximal to the second-order ducts, while extrahepatic cholangiocarcinoma or eCCA refers to tumors arising more distally (perihilar CCA, between second-order ducts and cystic duct and distal CCA, distal to cystic duct). Perihilar CCA represents 50% of the total CCAs, with distal lesions comprising 40% and the final 10% being intrahepatic. BTC are often diagnosed at advanced stages and have a grave outcome due to limited systemic options. Gemcitabine and cisplatin combination (GC) has been the first-line standard for more than a decade. Second-line chemotherapy (CT) options are limited. Targeted therapy or TT (fibroblast growth factor 2 inhibitors or FGFR2, isocitrate dehydrogenase 1 or IDH-1, and neurotrophic tyrosine receptor kinase or NTRK gene fusions inhibitors) have had reasonable success, but <5% of total BTC patients are eligible for them. The use of immune checkpoint inhibitors (ICI) such as pembrolizumab is restricted to microsatellite instability high (MSI-H) patients in the first line. The success of the TOPAZ-1 trial (GC plus durvalumab) is promising, with numerous trials underway that might soon bring targeted therapy (pemigatinib and infrigatinib) and ICI combinations (with CT or TT in microsatellite stable cancers) in the first line.

cholangiocarcinoma
gall bladder cancer
FGFR2
pemigatinib
infrigatinib
HER2
durvalumab
gemcitabine
NTRK
IDH

1. Introduction

Biliary tract cancers (BTC) comprise a group of malignancies originating in the epithelium of the biliary tract [1]. These include cholangiocarcinoma (CCA) and gallbladder carcinoma (GBC). Intrahepatic cholangiocarcinoma or iCCA refers to tumors proximal to the second-order ducts, while extrahepatic cholangiocarcinoma or eCCA refers to tumors arising more distally (perihilar CCA, between second-order ducts and cystic duct and distal CCA, distal to cystic duct) [2]. Perihilar CCA represents 50% of the total CCAs, with distal lesions comprising 40% and the final 10% being intrahepatic [3]. BTCs are relatively rare in developed countries, comprising approximately 3% of gastrointestinal malignancies with an incidence of 0.35 to 2 in 100,000 [4]. In developing countries such as China and Thailand, the incidence can be as high as 14–80 in 100,000. GBCs are less common, with an incidence of 1 in 100,000 in the USA but increasing as high as 27 in 100,000 in Chile ^[5][6][5,6]. Risk factors for CCAs include primary sclerosing cholangitis, choledochal cysts, cholelithiasis, hepatolithiasis, chronic liver disease, genetic conditions such as Lynch syndrome, BRCA mutations, cystic fibrosis, biliary papillomatosis, and liver fluke infection in endemic regions ^[7][8][7,8]. Risk factors for GBC include cholelithiasis, chronic infection with pathogens such as salmonella and Helicobacter pylori, obesity, and anatomical changes in the biliary tree [9]. The continued rise of CCAs, specifically iCCA, in the past four decades globally is concerning ^[10][11][12][10,11,12]. Its association with metabolic and infectious risk factors might be the primary reason for this dangerous trend.

A lack of robust screening measures, late diagnosis (unresectable to metastatic), challenging histology at presentations combined with limited systemic options, the high recurrence rate after surgery, and unreliable biomarkers to monitor the treatment response contribute to poor outcomes in BTCs [13]. Surgical management is curative in early-stage BTC, but it is feasible in only a small fraction of cases (≈30%) ^[14][15][14,15]. Therefore, the majority of the patients must be treated with systemic therapy and palliative intent. Even with resection, 3-year recurrence rates can be as high as 80% [16]. Liver transplant is approved for certain unresectable hilar or perihilar eCCA (≤3 cm, absent nodal and intra or extrahepatic metastatic disease and no biopsy) only [17].

2. Chemotherapy in Biliary Tract Cancers

2.1. Chemotherapy in the First Line

Over 70% BTCs present in advanced stages or aBTC (unresectable or metastatic) and are only eligible to receive palliative therapy. The combination of gemcitabine (Gem) and cisplatin (Cis), or GC, is the current approved first-line therapy [18]. There were no positive first-line trials for over a decade. The standard approach to BTCs is illustrated in Figure 1.

Figure 1. Current approach to biliary tract cancers. BTC—biliary tract cancers; MSI-H—microsatellite instability; MSS—microsatellite stable; GC—gemcitabine/cisplatin; FGFR2—fibroblast growth factor 2; IDH—isocitrate dehydrogenase-1; NTRK—neurotrophic tyrosine receptor kinase; HER2—human epidermal growth factor receptor 2 inhibitors; VEGF—vascular endothelial growth factor; TMB—tumor mutational burden; ATR—ataxia telangiectasia mutated and Rad3-related.

In ABC-01, a phase II randomized trial, GC combination was compared to Gem alone in treatment-naïve aBTC patients [19]. The tumor response rates (28% vs. 23%), time to progression (8 months vs. 4 months), and 6-month progression-free survival or PFS rate (57% vs. 46%) were higher in the combination group. GC approval in the first line was based on the ABC-02 trial, a phase III randomized control trial in which GC was compared to Gem alone. The median overall survival or OS (11.7 months vs. 8.1 months; hazard ratio or HR = 0.64; p < 0.001) and the median PFS (8 months vs. 5 months; HR = 0.63; p < 0.001) was higher in the GC group. The tumor control (complete response (CR) or partial response (PR) or stable disease (SD)) was also higher in the GC group (81% vs. 72%; p = 0.04). The tolerance profile was comparable between both groups, except for neutropenia (higher with GC). The combination of oxaliplatin, irinotecan, and infusional fluorouracil (mFOLFIRINOX) was inferior to GC in the first-line setting, as evidenced by the PRODIGE 38 AMEBICA trial [20]. In this randomized phase II/III trial, the 6-month PFS rate (44.6% in mFOLFIRINOX vs. 47.3% in GC), PFS (6.2 m vs. 7.4 m), and OS (11.7 m vs. 13.8 m) were superior in the GC group. A partially activated monophosphorylated Gem compound, NUC-1031, that can overcome the resistance developed against Gem, was tested in the first line for aBTC [21]. This compound does not need a nucleoside transporter to enter the cell, has enzyme-mediated activation, and resists degradation by cytidine deaminase [22]. Although early trials with NUC-1031 plus Cis had a greater objective response rate or ORR over GC (44% vs. 26%), the phase III trial was discontinued as the interim analysis showed that it would be unlikely to meet its primary end-point of 2.2 months superiority in OS compared to GC [21]. In the BREGO trial, Regorafenib (Reg) and GEMOX (gemcitabine and oxaliplatin combination) were compared to GEMOX alone in aBTC [23]. The overall results were unsatisfactory (the Reg-GEMOX group was not superior to the GEMOX-only group for PFS or OS). Subgroup analysis showed a higher disease control rate (or DCR), PFS, and OS in patients who continued Reg beyond four cycles. The addition of nab-paclitaxel (NP) to GC (GC/NP) in the first line had encouraging results in a single-arm phase II trial [24]. The hematological toxicity was very high in the first 32 (of 60) patients enrolled in the trial who received Gem (1000 mg/m²), Cis (25 mg/m²), and NP (125 mg/m²) on days 1 and 8 of 21-day cycles. The doses of Gem and NP were dropped to 800 and 100 mg/m², respectively, for the next 28 patients. The median PFS was 11.8 months and the median OS was 19.2 months. DCR (PR plus SD) was superior in the high-dose group (90% vs. 78% in reduced dose). Comparing GC and GC/NP is not ideal (no head–head trials), but GC/NP seems to have a better OS and PFS, and worse neutropenia and anemia, based on observations from the respective published trial data ^[18][24][18,24]. In a Korean retrospective review from four medical centers, the safety and efficacy of GC/NP in treating aBTC was reported last year [25]. The authors looked at the outcomes (ORR, DCR, PFS, and OS) in two groups of patients based on when they received GC/NP: a) in the first line; b) NP was added to GC before or after disease progression (PD). The former group’s ORR (48% vs. 31%) and DCR (90% vs. 75%) were superior. The ORR (40% vs. 16%) and DCR (86% vs. 60%) were greater when NP was added before PD in the latter group. The safety profile was acceptable in these patients and, as expected, Grade 3/4 events were lower in patients who received a reduced dose of GC/NP. A phase III randomized trial (SWOG1815, NCT03768414) is underway to examine the benefit of adding NP to GC in aBTC (GC/NP vs. GC). GC plus S-1 (an oral fluoropyrimidine derivative) combination has a survival benefit over GC in treating aBTCs [26]. The preliminary data of KHBO1401-MITSUBA, a phase III randomized trial, showed improved OS (13.5 months vs. 12.6 months), PFS (7.4 months vs. 5.5 months), and response rates (41% vs. 15%) in the triplet group compared to the GC group. In the TOPAZ-1 trial, phase III randomized, double-blind, placebo-controlled GC plus durvalumab (ICI) or GC-D was compared to GC plus a placebo [27]. Patients received GC-D for eight cycles (days 1 and 8, Q3W) followed by durvalumab only or placebo Q4W. The mOS 12.8 months vs. 11.5 months (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.66–0.97; p = 0.021), mPFS 7.2 months vs. 5.7 months (HR, 0.75; 95% CI, 0.64–0.89; p = 0.001), and ORR (26.7% vs. 18.7%) was superior in GC-D compared to the GC group. G3/4 AEs were similar in both groups. While the results of the GC-D combination are promising, thwe researchers need to wait for the full study data to make reliable conclusions. The results of other clinical trials are discussed in Table 1.

2.2. Chemotherapy in the Second Line

In aBTC (and ampullary cancers), patients who progressed on GC with a preserved performance status (Eastern Cooperative Oncology Group or ECOG scale of 0–1), FOLFOX had a small OS benefit (6.2 months vs. 5.3 months; adjusted hazard ratio = 0.69 [95% CI 0.50–0.97]; p = 0.031) compared to supportive care [28]. The survival rate was higher in the FOLFOX group at 6 months (51% vs. 36%) and 1 year (26% vs. 11%). Subgroup analysis in this trial produced some interesting results. The OS (not PFS) was superior with FOLFOX among the platinum-sensitive (PD after 90 days of completion of first-line chemotherapy) and platinum-resistant/refractory (PD on the first line or in less than 90 days after completion of first-line chemotherapy). Expectedly, high-grade AE were more prevalent in the FOLFOX group (69% vs. 52%). A retrospective study in Italy examined the differences in outcomes after second-line chemotherapy (post-GC) between elderly (≥70 years) and younger (<70 years) patients. There were no significant differences in the outcomes (OS or PFS) between the two groups. The most-used second-line agents in the elderly population were Gem alone or capecitabine alone or a combination of both. Treatment-related toxicity was very high in the elderly population compared to the younger group (48.5% vs. 8.2%; OR 6.31; p < 0.001) [29]. A combination of nanoliposomal irinotecan (Nan-Iri) and 5FU was compared to 5FU alone in the NIFTY trial [30]. It was a multicenter, open-label, randomized, phase IIb trial in which patients progressed on GC. The combination group had a superior PFS (7.1 m vs. 1.4 m; HR = 0.56; 95% CI 0.39–0.81; p = 0.0019) and ORR (19.3% vs. 2.1%) compared to the 5FU group. G3-4 neutropenia (24% vs. 1%) and serious adverse events (42% vs. 24%) occurred more in the combination group than the 5FU-only group. It was concluded that Nan-Iri plus 5-FU could be considered for second-line treatment in patients with BTC who formerly progressed on GC, especially in patients who cannot tolerate platinum agents. On the other hand, mFOLFIRINOX had reasonable efficacy and safety for patients who progressed on GC (≥3 cycles) and is an option for patients with no targetable mutations [31].

3. Targeted Therapy in Biliary Tract Cancers

Second-line options in patients who progressed on GC are limited. In the subset of patients with targetable mutations, fibroblast growth factor 2 (FGFR2) inhibitors such as those with pemigatinib and infrigatinib [32], neurotrophic tyrosine receptor kinase (NTRK) gene fusions such as larotrectinib and entrectinib ^[33][34][33,34], and isocitrate dehydrogenase 1 (IDH-1) with ivosidenib [35], are suitable agents which are preferred over chemotherapy in the second line (preferably after GC). Individual targeted therapy options will be discussed in the following text. The reported results of trials and ongoing trials with targeted therapy are summarized in Table 1 and Table 2.

Table 1.

Results of recent trials in biliary tract cancer.

	Line			Phase		(N)			Clinical Trial Identifier

# Part of a basket trial but these results are from the BTC cohort; * All grade AE, ** G1-G2 AE; BTC—biliary tract cancers include gall bladder cancers and CCA; iCCA—intrahepatic cholangiocarcinoma; eCCA—extra-hepatic cholangiocarcinoma; CCA—cholangiocarcinoma includes iCCA and eCCA; AC—ampullary cancer; GC—gemcitabine/cisplatin; Gem/Ox—gemcitabine/oxaliplatin; OS—median overall survival; PFS—median progression free survival; m—months; wks—weeks; HR—hazard ratio; CI—confidence interval; TRAEs—treatment-related adverse events; NR—not reached; DCR—disease control rate; ORR—objective response rate; CR—complete response; PR—partial response; DOR—duration of response; IDH—isocitrate dehydrogenase-1; VEGF—vascular endothelial growth factor; FGFR2—fibroblast growth factor 2; HER2—human epidermal growth factor receptor 2 inhibitors; EGFR—epidermal growth factor receptor; mab—monoclonal antibody; TGF—transforming growth factor; PD-1—programmed cell death protein 1; PDL1—programmed cell death ligand protein; TKI—tyrosine kinase inhibitor; DLT—dose limiting toxicity; MTD—maximum tolerated dose; R2PD—recommended phase II dose.

Table 2.

Ongoing trials with targeted therapy in biliary tract cancer.

	Line			Phase			Clinical Trial Identifier		Treated Cancer Group			Target of the Drug		Experimental Arm				Treated Cancer Group		Target of the Drug (If Applicable)				Experimental Arm		Comparative Arm			Comparative Arm		Primary Outcome Studied in the Trial			Top 3 Treatment-Related Adverse Events			Notes
	Primary Outcome			Secondary Outcome (Main)

Ongoing trials with immunotherapy in biliary tract cancer.

	Line			Phase			Clinical Trial Identifier			Treated Cancer Group			Experimental Arm			Comparative Arm			Primary Outcome			Secondary Outcome (Main)
	First line			III			NCT03875235 [27]
				First line		BTC				Durvalumab (D) + GC			PD-1			GC + placebo (Pbo)			OS—12.8 m vs. 11.5 m (D vs. Pbo, HR = 0.80; 95% CI, 0.66–0.97; p = 0.021)			Anemia		Low neutrophil count		Low platelet count			PFS-7.2 m vs. 5.7 m (D vs. Pbo, HR, 0.75; 95% CI, 0.64–0.89; p = 0.001); ORR—26.7% vs. 18.7% (D vs. Pbo); Grade 3/4—62.7% vs. 64.9% (D vs. Pbo)
						III				II			NCT03796429 [36]			BTC
						First line				III		NCT03773302				NCT04003636		FGFR rearrangement			Toripalimab + GC			PD-1			Single arm			PFS—6.7 m		OS—NR			Leukopenia		Anemia		Rash			ORR—21		DCR—85%		G3/4, non-hematological in 20% and hematological—69%
										II			NCT03951597 [37]			iCCA			Toripalimab + lenvatinib + GemOx +			HAIC (oxaliplatin + 5-FU) + toripalimab (T) + bevacizumab		PD-1 + TKI			None		Single arm			PFS, ORR		ORR—80% (1CR and three patients obtained enough control to allow for resection)			Jaundice		Rash		Proteinuria			OS, AE, CA 19-9, DCE-MRI signal change, DWI MRI signal change		DCR—93.3%,		PFS—10 m		OS—NR		DOR—9.8 m
											II
				II					NCT04361331 [38]				NCT04172402		iCCA			BTC		Lenvatinib + GemOx			TKI		TS-1 + gemcitabine + nivolumab				None		Single arm			ORR		ORR—30%		1/30 was down staged to have resection			Fatigue		Jaundice		Vomiting			PFS and OS—NR		DCRc—87%		No G5, ≥G3 in 40%
BTC			CCA						Pembrolizumab + GC		Pemigatinib			GC + placebo		GC				OS		PFS				PFS, ORR, DOR		OS, OR, DOR, DCR
	III			NCT03773302						FGFR2 fusion/translocation			CCA
	II/III			NCT04066491					Infrigatinib				BTC		GC			Bintrafusp alfa		PFS			GC + placebo		OS. DCR, DOR, BOR
	OS		DLT						PFS, DOR, ORR			III			NCT04093362			iCCA with FGFR2			iCCA
	II		Futibatinib						GC			PFS			ORR. DCR. OS. Safety/Tolerability
	II			NCT03768414						Not specific			BTC			GC/NP			GC			OS			PFS, ORR, DCR			None specified			Ib		II			NCT02992340			BTC			Varlitinib + GC			Pan-HER 2
	II
	II		NCT03579771			NCT03898895		High risk *			iCCA		Single arm			Resectable IHC		DLT—1/11 (200 mg); 1/12 (300 mg)				GC/NP			Camrelizumab + radiotherapy		None			SR		blood and lymphatic system disorders			PR = 8/23; SD = 12/23		ORR—35%, DCR—87%, DoR—4 m, PFS—6.8 m
	RR, R0; OS; PFS			GC			PFS			OS, AE, tumor response			Ib		II
	III		NCT02128282 [39]			CCA			Silmitasertib (CX-4945) + GC			Casein kinase 2 (CK2)
	Subsequent lines		k		Single arm				II		PFS 11 m				NCT03478488		NCT04722133			Diarrhea	BTC		HER 2			aBTC		KN035 (PD-L1 antibody) + gemcitabine + oxaliplatin		Neutropenia		Nausea				Trastuzumab-pkrb + FOLFOX		Compared to GC—Better PFS		None		Lesser neutropenia
						GEMOX				OS	ORR				PFS, ORR, DCR, DOR, TTP		PFS, OS, DCR, incidence of TRAE			I			NCT02375880
					II	[40]			jRCT2031180150		BTC			HER 2		DKN-01 + GC			Dickkopf-1 (DKK1)			Single arm			Safety—no DLT			Advanced solid tumors ^#		Neutropenia		Thrombocytopenia		Leukopenia
					II				NCT03796429			BTC		Trastuzumab and pertuzumab			Gemcitabine/S-1 + toripalimab			None		None			PFS, OS			ORR		ORR—21.3%		PFS, OS, DoR, safety		ORR, Safety		PFS—8.7 m
					Subsequent lines
									II		III				NCT02091141		NCT02989857 (ClarIDHy) [
									II			NCT0402776441]		(My Pathway)		CCA				HER 2			BTC		BTC		^#		Ivosidenib (IVO)				Trastuzumab and pertuzumab		IDH-1		Toripalimab + S1 and albumin paclitaxel		None		IVO alone vs.		placebo				None		ORR		PFS—2.7 m vs. 1.4 m (HR = 0.37; 95% CI 0.25–0.54; p < 0.0001).				ORRDCR, PFS, OS, AE		Ascites		Fatigue	Anemia		OS in updated analysis 10.3 m IVO vs. 7.5 m (HR = 0.79; 95% CI 0.56–1.12; p = 0.093)
										PFS, DCR, OS			II
									II		NCT02966821 [42]			BTC			NCT04466891		Surufatinib				HER 2			BTC		VEGF			Zanidatamab monotherapy		Single arm
									II			NCT04191343			BTC		None		Toripalimab + GEMOX		PFS rate at 16 wks—46.33% (95%, 24.38–65.73)			None		ORR		Elevated bilirubin		Hypertension Proteinuria				ORR		DoR; DoR > 16 wks; DCR, PFS, OS; incidence of TRAE, PK		PFS—3.7 m		OS—6.9 m
									None specified			II
									II		ChiCTR1900022003 [43].
									II			NCT02999672		BTC			NCT04300959		HER 2			BTC		Anlotinib +		sintlimab			CCA ^#		Anlotinib hydrochloride + PD1 + gemcitabine + cisplatin		TKI + PD-1				Trastuzumab emtansine			Gemcitabine Cisplatin		Single arm				None		OS—NR				OS 1 yr		BOR			OS 2 yr, PFS, ORR, AE		Hypertension **	Diarrhea	Hypothyroidism		PFS—6.5 m	ORR—40%	DCR—87%
									PFS, OS, TRAE, SAE, PK			II			NCT02052778 [44].			iCCA #
									II			Futibatinib
										Subsequent lines			NCT04482309			II			NCT03482102FGFR2			HER2			BTC ^#			Trastuzumab deruxtecan		HCC, BTC		Single arm			Tremelimumab + durvalumab + radiation		ORR 37%			None		Hyperphosphatemia			None		ORR			ORR			AE, OS, DCR, PFS, DOR, TTP Diarrhea *		Dry mouth *			DoR—8.3 m and DCR = 82%
												DOR, DCR, PFF, OS, AEs, PK and immunogenicity				II			NCT03230318 [45]			iCCA
					II							NCT03839342.			Non-V600E BRAF mutations		Derazantinib			Advanced solid tumors ^#		FGFR2—mutations and amplifications
					II							NCT04238637			BTC		Single arm				Durvalumab (D) vs. D + T			3-month PFS rate—76%				Bimimetinib + encorafenib		NoneNot specified			None			ORR		ORR			Safety, DCR, PFS		DCR = 80%		PFS = 7.3 m		6-month PFS rate = 50%
						II							NCT03797326 [46]
				Safety, DoR, PFS, OS					II
					II				NCT02428855					NCT02821754		BTC #				IDH1 mutation		Pembrolizumab + lenvatinib			iCCA		PD-1 + TKI			Dasatinib		Single arm			None		ORR—10%		Safety—TRAE in 97% (>G354%)			ORR		Hypertension Dysphonia Diarrhea				PFS, OS, TRAE		DCR—68%		PFS—6.1 m		OS—8.6 m
					HCC, BTC							D + T			D +T + TACE		D + T + RFA		D + T + Cryo			PFS			Safety		II
						II						NCT02265341 [47]			NCT02675829
					II				BTC						NCT02703714		HER2 amplification		Ponatinib			Advanced solid tumors		FGFR2		^#		Single arm			ORR—9%				BTC			PembrolizumabLymphopenia, Rash		Fatigue (50%)				and sargramostim (GM-CSF)		Ado-Trastuzumab emtansine			None		None		CR = 0, PR—8%, SD = 36%. PFS—2.4 m and OS—15.7 m
					ORR				ORR						None		AE, PD-L1 positivity, PFS, OS, DOR			II			NCT03834220
	II	[48]		NCT03207347		CCA among Solid tumors						BAP1 and other DDR genes		Debio 1347
	I/II			NCT03937895			BTC *					FGFR Fusion			Allogeneic natural killer cells + pembrolizumab		Single arm			ORR—2/5 (40%) of CCA			CCA ^#		None		Fatigue		Hyperphosphatemia		Anemia				Niraparib			None		DoR and PFS were 16.1 weeks and 18.3 weeks (in all patients), respectively.
	Phase I—DLT		Phase II—ORR			ORR						TTP, toxicity		PFS, OS, TRAE			II			NCT01953926
	II	[49]		NCT03212274		BTC + AC #
	II		IDH1/2 mutation		Neratinib				HER2 or EGFR Exon 18						NCT04306367Single arm				BTC				ORR			OS, PFS, TRAE, DoR
	NCT04217954			CCA		Pembrolizumab and olaparib			ORR—12%					Olaprib			mFOLFOX-historical control		Diarrhea *		Vomiting *			None		PSS—2.8 m		OS—5.4 m
	ORR				ORR		PFS, OS, safety						DOR, PFS, OS, safety			I/ II
	II
	II		NCT01752920 [50]				NCT04042831			iCCA		NCT04295317		DNA repair gene mutation			iCCA—adjuvant		Derazantinib			FGFR2—fusions			Single arm			BTC		Safety—all-grade TRAE in 93%				PD-1 blocking antibody SHR-1210 + capecitabine			None		Fatigue		Eye-toxicity		Hyperphospatemia				Olaparib		≥3 Grade TRAE in 28%		PFS			OS, side effects		ORR—27%		DCR—83%
		I			II		NCT02699515 [51]			NCT03207347		BTC #				DNA repair gene mutation		Bintrafusp alfa,				CCA ^#		TGF-β and PD-L1			Niraparib		Single arm
		None			Safety—emergent and all adverse events		ORR			OS, PFS, TRAEs
	BTC			None		II				NCT03250273		Rash		Fever		Increased lipase			63% had TRAE		37% ≥ G3
	BTC, PDA			Entinostat + nivolumab			None			ORR			Toxicity, PFS, OS, DOR			I			II		NCT02892123
	II	[52]		NCT02162914		BTC #				NCT02866383		ZW25 (Zanidatamab)				BTC, PDA			Nivolumab + ipilimumab + radiotherapy		bispecific HER2			Single arm			VEGF mutation			Nivolumab + radiotherapySafety/tolerability—only G1–G2 reported in 70%			Fatigue **		CBR		Diarrhea		Infusion reaction			ORR—47		DCR—65%		DoR—6.6 m
	CCA			Regorafenib			None			PFS			RR, OS			AE, ORR, PFS, OS, QOL			Ib
	II		NCT03996408 [53]			NCT03339843		BTC				CDK 4/6 mutation		Anlotinib		TQB2450
	II			CCA		NCT04057365		^#		TKI + PDL1			Abemaciclib		Single arm			BTC		None			DKN-01 + nivolumab		DLT/ MTD		None		in first 3 weeks (one cycle)—none		RP2D—25 mg		ORR—42%				ORR		Anti-tumor activity			PFS, OS		* Hypertension		Leukopenia		Increased total bilirubin		Neutropenia			PFS—240 days			PFS, OS, toxicity DCR—75%


II


NCT04003896


CDK 4/6 mutation


II

	NCT03639935			BTC		BTC			Rucaparib + nivolumab		Abemaciclib			None		None				4-month PFS rate		ORR			PFS, DCR, OS, QoL
	Response rate, PFS, OS			II
	II		NCT02232633			NCT04299581		STAT3 inhibitor			CCA			BBI503				iCCA			Camrelizumab + cryoNone				None		DCR				ORRORR, OS, PFS, PK TRAE
		DOR, PFS, OS, DCR, AE			II			NCT03878095			IDH1/2 mutation			CCA ^#
	II		Ceralasertib + olaparib			None			ORR			PFS, OS, DoR, Safety
	NCT03999658			BTC ^#			STI-3031		anti-PD-L1 antibody			None			ORR			DOR, CR, PFS, 1-year PFS rate, correlative studies			I/II			NCT02273739			IDH2 mutation			Advanced solid tumors ^#			Enasidenib		Enasidenib
	II			NCT03801083		None			DLT, ECOG			BTC		Plasma concentration metrics
	Tumor infiltrating lymphocytes (TIL) + aldesleukin			None			ORR			CRR, DOR, DCR, PFS, OS, QOL			I			NCT04764084			HRR mutations			CCA ^#			Niraparib + anlotinib			None			DLT, MTD			ORR, PFS
	I/II			NCT03684811			BTC ^#			FT-2102 vs. FT-2102 + nivolumab			None			DLT, Dose, ORR			ORR, AE, PFS, TTP, DOR, OS, TT			I			NCT04521686
	I/II		IDH1 R132-mutant advanced solid tumor types or circulating tumor DNA IDH2 R140 or IDH2 R172 mutation (CCA)		NCT03475953			BTC ^#		CCA ^#			Regorafenib + avelumab		LY3410738		LY3410738 + GC					None			I = dose		II = antitumor activity		Maximum tolerated dose			MTD, DLT, toxicity, AE, PK and correlative studies		ORR		Safety and tolerability		Efficacy		PK properties
	I			NCT02381886			IDH1 mutation			BTC ^#			IDH305			None
	I/II					NCT03785873			BTCDLT			TRAE, PK, delta 2-hydroxyglutarate, ORR, SAE
	Nal-Irinotecan + nivolumab + 5-Fluorouracil + leucovorin			None			I = DLT		II = PFS			AE, ORR, OS			I			NCT03272464			BRAF-V600E			BTC ^#			JSI-1187 + dabrafenib			None
	I			NCT03849469			iCCA ^#			XmAb^®22841 and pembrolizumab			XmAb^®22841 Monotherapy		TRAE			Safety and tolerability		DOR, OS, PFS, TTP
	None			I
	I		NCT04190628				NCT03257761		BRAF-V600E			BTC, PDA, HCC		BTC ^#				Guadecitabine + durvalumab		ABM-1310 + cobimetinib			None		None			AE, Tumor response		MTD			OS, PFS		TRAE, PK, DOR, OS, PFS, TTP
	I			NCT02451553			No specific target			BTC ^#			Afatinib dimaleate + capecitabine			None			AE, DLT, MTD			DOR, OS, PFS, RR, TTP, biomarker profile
	I			NCT03507998			Wnt/β-catenin signaling inhibitors			BTC ^#			CGX1321			None			TRAE			PK

^# Basket trial; * T-stage ≥ Ib (Ib-IV); solitary lesion > 5 cm; Multifocal tumors or satellite lesions present; BTC—biliary tract cancers include gall bladder cancers and CCA; iCCA—intrahepatic cholangiocarcinoma; eCCA—extra-hepatic cholangiocarcinoma; CCA—cholangiocarcinoma includes iCCA and eCCA; FGFR2—fibroblast growth factor 2; IDH—isocitrate dehydrogenase-1; VEGF—vascular endothelial growth factor; HER2—human epidermal growth factor receptor 2 inhibitors; STAT—signal transducer and activator of transcription; GC—gemcitabine/cisplatin; DCR—disease control rate; ORR—objective response rate; BOR—best overall response; DOR—duration of response; TTP—time to progression; SR—surgical resect ability; TRAEs—treatment-related adverse events; SAE—serious adverse events; PK—pharmacokinetics; RR—response rate; DLT—dose limiting toxicity MTD—maximum tolerated dose; QoL—quality of life; BOR—best overall response.

4. Immunotherapy in Biliary Tract Cancers

In the current clinical practice, immunotherapy can be broadly divided into ICIs and less explored adoptive cell therapy (chimeric antigen receptor T cell therapy or CAR-T) and vaccines. Reported results and ongoing trials with immunotherapy are summarized in Table 1 (above) and Table 3 (below).

Table 3.

BTC—biliary tract cancers include gall bladder cancers and CCA; iCCA—intrahepatic cholangiocarcinoma; eCCA—extra-hepatic cholangiocarcinoma; CCA—cholangiocarcinoma includes iCCA and eCCA; PDA—pancreatic cancer; HCC—hepatocellular cancer; FGFR2—fibroblast growth factor 2; IDH—isocitrate dehydrogenase-1; VEGF—vascular endothelial growth factor; HER2—human epidermal growth factor receptor 2 inhibitors; HHR—homologous recombination repair; GC—gemcitabine/cisplatin; GM-CSF—granulocyte-macrophage colony-stimulating factor; TACE—transcatheter arterial chemoembolization; RFA—radiofrequency ablation; Cryo—cryotherapy; HAIC—hepatic arterial infusion chemotherapy; CPS—combined positive score; MSI-H—microsatellite instability; DCE—dynamic contrast enhanced; DWI—diffusion weighted imaging; TTP—time to progression; CBR—clinical benefit rate; QOL—quality of life; TTR—time to response; ^#—basket trials with BTC among them; * at least 1% CPS PD-L1 or MSI-high or dMMR positive.

5. Systemic Therapy in Early-Stage Biliary Tract Cancers

Capecitabine is the preferred agent for AT in BTCs based on the BILCAP trial ^[54][138]. On the other hand, BCAT and PRODIGE 12 trials could not show the clinical benefit of gemcitabine or gemcitabine/oxaliplatin combination over observation ^[55][56][57][139,140,141]. A recently presented pooled analysis of these two trials further proved this point ^[58][142]. A total of 419 patients were included in the two studies, which showed no difference in PFS (2.9 years in gem-based vs. 2.1 years in observation; HR = 0.91; p = 0.45) or OS (5.1 years vs. 5 years; HR = 1.03; p = 0.83). Radiation alone (XRT) or chemoradiation (CRT) in the adjuvant setting is not a popular approach in managing BTC. CRT is offered to eCCA and GBC patients with positive margins or lymph nodes ^[59][60][61][143,144,145]. Retrospective studies showed benefits with chemotherapy only in resected BTCs, but it is difficult to compare the AT strategies as CRT or XRT is offered to BTCs with high-risk factors (positive margins/lymph nodes) ^[62][146].

Neoadjuvant (NAT) systemic therapy is not a standard approach in resectable BTCs. Some case reports and retrospective studies show the benefit of NAT downstaging the locally advanced or unresectable BTCs enough to have resection ^[63][64][65][147,148,149]. The addition of pre-operative radiation can increase the probability of R0 resection in these tumors ^[66][67][150,151]. On the other hand, NAT did not result in any survival advantage in managing resectable BTCs in the reported studies ^[68][152]. Multiple trials investigating the role of neoadjuvant therapy in resectable (GC-D in NCT04308174 or DEBATE; GC in NCT03673072; GC/NP in NCT03579771) and unresectable/locally advanced BTCs (FOLOXIRI in NCT03603834; toripalimab + GEMOX + lenvatinib in NCT0450628) are underway that may give us a definite answer in the coming years. In the current practice, systemic options typically for NAT are similar to those used for treating aBTCs (such as GC).

Locoregional therapy (LRT) with high-dose XRT (58–67.5 Gy in 15 fractions) and SBRT (30–50 Gy in 3 to 5 fractions) improves local control and OS in unresectable iCCA, and can be an option for suitable patients ^[69][70][153,154]. Other LRTs such as transcatheter arterial chemoembolization (TACE) and transarterial radioembolization (TARE) are not typically employed in treating BTCs. SBRT plus capecitabine combination increased local control rates (≈80%) with minimal toxicity (no ≥ grade 3 toxicity) in unresectable perihilar CCA ^[71][155]. Other trials intended to see the benefit of SBRT and chemotherapy combinations were closed due to low accrual (NCT01151761 and NCT00983541). ICI with TACE or SBRT, or TARE trials, are underway (NCT03898895, NCT04866836, NCT03937830, NCT02821754, NCT04238637, and NCT04708067), which may open up more options in the near future.