Biliary tract cancer management - now and future

Biliary tract cancer management - now and future: Comparison

Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Ashish Manne.

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, we 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^[33][34],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

Treated Cancer Group

Experimental Arm

Target of the Drug (If Applicable)

Comparative Arm

# 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	Target of the Drug	Treated Cancer Group	Experimental Arm	Primary Outcome Studied in the Trial	Top 3 Treatment-Related Adverse Events	Notes
	Comparative Arm			Primary Outcome			Secondary Outcome (Main)
First line	III	NCT03875235 ^[27
	First line	III	^]	NCT03773302	FGFR rearrangement	CCA	Pemigatinib	GC	PFS	OS, OR, DOR, DCR
		None
				PFS, ORR			OS, AE, CA 19-9, DCE-MRI signal change, DWI MRI signal change
		II	NCT04172402	BTC	TS-1 + gemcitabine + nivolumab	None
		^#


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.

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)
	BTC
First line	III	NCT04003636		Durvalumab (D) + GC	BTC 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		Pembrolizumab + GC 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)
		GC + placebo			OS			PFS, ORR, DOR	II	III NCT03796429 ^[36]	BTC	Toripalimab + GC	PD-1		NCT03773302 Single arm	PFS—6.7 m OS—NR	Leukopenia Anemia	FGFR2 fusion/translocation Rash	CCA	Infrigatinib
	II/III	NCT04066491		GC			PFS	OS. DCR, DOR, BOR
		BTC		Bintrafusp alfa	GC + placebo		ORR—21		DCR—85% G3/4, non-hematological in 20% and hematological—69%
		OS		DLT			PFS, DOR, ORR	II	III NCT03951597 ^[37]	iCCA
	II	NCT04093362		NCT04217954 iCCA with FGFR2Toripalimab + lenvatinib + GemOx +		iCCA PD-1 + TKI	Single arm	Futibatinib ORR—80% (1CR and three patients obtained enough control to allow for resection)		GC Jaundice Rash	PFS Proteinuria	ORR. DCR. OS. Safety/Tolerability
		BTC		HAIC (oxaliplatin + 5-FU) + toripalimab (T) + bevacizumab		DCR—93.3%,		PFS—10 m	OS—NR DOR—9.8 m
			II	NCT04361331 ^[38]	iCCA	Lenvatinib + GemOx	TKI	Single arm	II	NCT03768414	Not specific ORR—30%	BTC 1/30 was down staged to have resection	Fatigue Jaundice Vomiting	PFS and OS—NR DCRc—87% No G5, ≥G3 in 40%
			GC/NP			GC		ORR OS	None specified PFS, ORR, DCR		Ib II	NCT02992340	BTC	Varlitinib + GC	Pan-HER 2
	II		Single arm			DLT—1/11 (200 mg); 1/12 (300 mg)		blood and lymphatic system disorders	NCT03579771 PR = 8/23; SD = 12/23 ORR—35%, DCR—87%, DoR—4 m, PFS—6.8 m
	High risk *
II		Resectable IHC			NCT03898895 GC/NP	None	SR	RR, R0; OS; PFS	iCCA	Camrelizumab + radiotherapy	GC	PFS	OS, AE, tumor response	Ib II	NCT02128282 ^[39]	CCA	Silmitasertib (CX-4945) + GC	Casein kinase 2 (CK2)
Subsequent lines k
	III		Single arm			II	PFS 11 m		NCT04722133	HER 2	aBTC	Trastuzumab-pkrb + FOLFOX	NCT03478488		BTC	KN035 (PD-L1 antibody) + gemcitabine + oxaliplatin	GEMOX None	OS	PFS, ORR, DCR, DOR, TTP Diarrhea Neutropenia Nausea	ORR Compared to GC—Better PFS Lesser neutropenia
		PFS, OS, DCR, incidence of TRAE		I		NCT02375880
	II	^[40]	BTC	DKN-01 + GC		jRCT2031180150 Dickkopf-1 (DKK1)	Single arm	Safety—no DLT	Neutropenia Thrombocytopenia Leukopenia	ORR—21.3% PFS—8.7 m
		HER 2		Advanced solid tumors ^#		Trastuzumab and pertuzumab	None	ORR	PFS, OS, DoR, safety
	II	NCT03796429	BTC	Gemcitabine/S-1 + toripalimab		None	Subsequent lines
		PFS, OS				ORR, Safety			II III		NCT02091141 NCT02989857 (ClarIDHy)
	II	NCT04027764	^[41]	(My Pathway)		BTC CCA			HER 2	Toripalimab + S1 and albumin paclitaxel Ivosidenib (IVO)	IDH-1	IVO alone vs.	BTC ^#	None	ORR placebo	PFS—2.7 m vs. 1.4 m (HR = 0.37; 95% CI 0.25–0.54; p < 0.0001).		PFS, DCR, OS 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)
		Trastuzumab and pertuzumab	II	NCT02966821
	II	^[42]	NCT04191343 BTC			BTCSurufatinib		VEGF	Toripalimab + GEMOX		None Single arm	ORR PFS rate at 16 wks—46.33% (95%, 24.38–65.73)	None specified Elevated bilirubin Hypertension Proteinuria	PFS—3.7 m OS—6.9 m
	II	ChiCTR1900022003 ^[43].	BTC	Anlotinib + sintlimab		TKI + PD-1		Single arm	OS—NR	Hypertension ** Diarrhea Hypothyroidism	PFS—6.5 m ORR—40% DCR—87%
			None					ORR		DCR, PFS, OS, AE
	II	NCT04466891	HER 2	BTC		Zanidatamab monotherapy		None	ORR	DoR; DoR > 16 wks; DCR, PFS, OS; incidence of TRAE, PK
	II	NCT02999672	HER 2	CCA ^#
	II	NCT04300959		BTC		Anlotinib hydrochloride + PD1 + gemcitabine + cisplatinTrastuzumab emtansine		None	BOR	Gemcitabine Cisplatin	PFS, OS, TRAE, SAE, PK	OS 1 yr	OS 2 yr, PFS, ORR, AE	II	NCT02052778 ^[44].	iCCA #	Futibatinib	FGFR2	Single arm	ORR 37%	Hyperphosphatemia Diarrhea *
	II	NCT04482309		HER2		Dry mouth *		BTC ^#		Trastuzumab deruxtecan	None	ORR DoR—8.3 m and DCR = 82%
		DOR, DCR, PFF, OS, AEs, PK and immunogenicity		II		NCT03230318 ^[45]		iCCA	Derazantinib	FGFR2—mutations and amplifications	Single arm	3-month PFS rate—76%	Not specified
	II	NCT03839342.		Non-V600E BRAF mutations		DCR = 80%		Advanced solid tumors ^#	Bimimetinib + encorafenib		None PFS = 7.3 m	ORR 6-month PFS rate = 50%
		Safety, DCR, PFS		II		NCT03797326 ^[46]
	Subsequent lines	II	NCT03482102	HCC, BTC		Tremelimumab + durvalumab + radiation	None	ORR	AE, OS, DCR, PFS, DOR, TTP
		II	NCT04238637	BTC		Durvalumab (D) vs. D + T	None	ORR		BTC #
			Safety, DoR, PFS, OS			II
		II	NCT02428855			IDH1 mutation	NCT02821754	Pembrolizumab + lenvatinib	HCC, BTC iCCA	D + T PD-1 + TKI	Dasatinib Single arm		D +T + TACE D + T + RFANone ORR—10% Safety—TRAE in 97% (>G354%)	ORR Hypertension Dysphonia Diarrhea		D + T + Cryo PFS, OS, TRAE	PFS DCR—68% PFS—6.1 m OS—8.6 m
			Safety			II	NCT02265341 ^[47]	BTC
		II	NCT02675829
		II				Ponatinib		NCT02703714 HER2 amplification FGFR2	Advanced solid tumors ^# Single arm	BTC ORR—9%	Lymphopenia, Rash Fatigue (50%)		Pembrolizumab and sargramostim (GM-CSF) Ado-Trastuzumab emtansine	None CR = 0, PR—8%, SD = 36%. PFS—2.4 m and OS—15.7 m
			None				ORR	ORR	None		AE, PD-L1 positivity, PFS, OS, DOR	II	NCT03834220 ^[48]	CCA among Solid tumors
II
I/II		NCT03207347	Debio 1347		NCT03937895 BAP1 and other DDR genes	CCA	BTC * ^#	Allogeneic natural killer cells + pembrolizumab FGFR Fusion	Niraparib Single arm	None ORR—2/5 (40%) of CCA		None ORR Fatigue Hyperphosphatemia Anemia	DoR and PFS were 16.1 weeks and 18.3 weeks (in all patients), respectively.
			Phase I—DLT		PFS, OS, TRAE		Phase II—ORR	TTP, toxicity	II	NCT01953926 ^[49]	BTC + AC #
II		NCT03212274	Neratinib		IDH1/2 mutation	CCA HER2 or EGFR Exon 18		Olaprib Single arm
II		NCT04306367		None			ORR—12%	BTC ORR	Pembrolizumab and olaparib Diarrhea * Vomiting *	PSS—2.8 m	mFOLFOX-historical control PFS, OS, safety OS—5.4 m
			ORR			DOR, PFS, OS, safety		I/ II	NCT01752920 ^[50]	iCCA	Derazantinib	FGFR2—fusions	Single arm	Safety—all-grade TRAE in 93%	Fatigue Eye-toxicity Hyperphospatemia
II		NCT04042831
II			DNA repair gene mutation		NCT04295317BTC		Olaparib	≥3 Grade TRAE in 28%		iCCA—adjuvant	PD-1 blocking antibody SHR-1210 + capecitabine None	None		PFS ORR ORR—27%	OS, side effects DCR—83%
		OS, PFS, TRAE, DoR		I	NCT02699515 ^[51]
II			BTC #
II		NCT03207347	NCT03250273	Bintrafusp alfa,		BTC, PDA	TGF-β and PD-L1	Entinostat + nivolumab Single arm	DNA repair gene mutation Safety—emergent and all adverse events	None		ORR Rash Fever Increased lipase	63% had TRAE	CCA ^#	Niraparib 37% ≥ G3
	None			ORR			OS, PFS, TRAEs	Toxicity, PFS, OS, DOR	I	NCT02892123 ^[52]	BTC #	ZW25 (Zanidatamab)	bispecific HER2
II	NCT02866383	BTC, PDA	Nivolumab + ipilimumab + radiotherapy		Single arm	Safety/tolerability—only G1–G2 reported in 70%	Fatigue ** Diarrhea Infusion reaction	ORR—47 DCR—65% DoR—6.6 m
Ib	NCT03996408 ^[53]	BTC	Anlotinib TQB2450	TKI + PDL1
II	NCT02162914	VEGF mutation	CCA	Regorafenib		Nivolumab + radiotherapy None	CBR PFS	AE, ORR, PFS, OS, QOL RR, OS		Single arm
II	NCT03339843
II		CDK 4/6 mutation	DLT/ MTD		NCT04057365CCA ^#	Abemaciclib		BTC None	DKN-01 + nivolumab in first 3 weeks (one cycle)—none RP2D—25 mg	None ORR—42%		ORR	* Hypertension Leukopenia Increased total bilirubin Neutropenia	PFS—240 days DCR—75%

Anti-tumor activity

PFS, OS

PFS, OS, toxicity

NCT04003896

CDK 4/6 mutation

BTC

Abemaciclib

None

NCT03639935

BTC

Rucaparib + nivolumab

None

4-month PFS rate

ORR

PFS, DCR, OS, QoL

Response rate, PFS, OS

NCT02232633

NCT04299581

STAT3 inhibitor

iCCACCA

BBI503

None

Camrelizumab + cryo

None

ORR

DCR

DOR, PFS, OS, DCR, AE

ORR, OS, PFS, PK TRAE

NCT03878095

NCT03999658

IDH1/2 mutation

CCA ^#

BTC Ceralasertib + olaparib

None

ORR

STI-3031

anti-PD-L1 antibody

PFS, OS, DoR, Safety

None

ORR

DOR, CR, PFS, 1-year PFS rate, correlative studies

I/II

NCT02273739

IDH2 mutation

Advanced solid tumors ^#

Enasidenib

None

DLT, ECOG

Plasma concentration metrics

NCT03801083

BTC

Tumor infiltrating lymphocytes (TIL) + aldesleukin

None

ORR

CRR, DOR, DCR, PFS, OS, QOL

I/II

NCT04764084

NCT03684811

HRR mutations

BTC ^#

CCA ^#

FT-2102 vs. FT-2102 + nivolumab

Niraparib + anlotinib

None

DLT, MTD

ORR, PFS

DLT, Dose, ORR

ORR, AE, PFS, TTP, DOR, OS, TT

NCT04521686

IDH1 R132-mutant advanced solid tumor types or circulating tumor DNA IDH2 R140 or IDH2 R172 mutation (CCA)

CCA ^#

LY3410738

LY3410738 + GC

Maximum tolerated dose

I/II

NCT03475953

BTC ^#

Regorafenib + avelumab

None

I = dose

II = antitumor activity

ORR

MTD, DLT, toxicity, AE, PK and correlative studies

Safety and tolerability

Efficacy

PK properties

NCT02381886

IDH1 mutation

BTC

I/II

NCT03785873

BTC

IDH305

None

Nal-Irinotecan + nivolumab + 5-Fluorouracil + leucovorin

DLT

NoneTRAE, PK, delta 2-hydroxyglutarate, ORR, SAE

I = DLT

II = PFS

AE, ORR, OS

NCT03272464

NCT03849469

BRAF-V600E

iCCA ^#

BTC ^#

XmAb^®22841 and pembrolizumab

JSI-1187 + dabrafenib

XmAb^®22841 Monotherapy

None

TRAE

DOR, OS, PFS, TTP

Safety and tolerability

None

NCT04190628

NCT03257761

BRAF-V600E

BTC ^#

BTC, PDA, HCCABM-1310 + cobimetinib

None

Guadecitabine + durvalumab

None

AE, Tumor response

MTD

TRAE, PK, DOR, OS, PFS, TTP

OS, PFS

NCT02451553

No specific target

BTC ^#

Afatinib dimaleate + capecitabine

None

AE, DLT, MTD

DOR, OS, PFS, RR, TTP, biomarker profile

NCT03507998

Wnt/β-catenin signaling inhibitors

BTC

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 [138]^[54]. On the other hand, BCAT and PRODIGE 12 trials could not show the clinical benefit of gemcitabine or gemcitabine/oxaliplatin combination over observation [139,140,141]^[55][56][57]. A recently presented pooled analysis of these two trials further proved this point [142]^[58]. 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 [143,144,145]^[59][60][61]. 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) [146]^[62].

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 [147,148,149]^[63][64][65]. The addition of pre-operative radiation can increase the probability of R0 resection in these tumors [150,151]^[66][67]. On the other hand, NAT did not result in any survival advantage in managing resectable BTCs in the reported studies [152]^[68]. 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 [153,154]^[69][70]. 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 [155]^[71]. 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.

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