Biliary tract cancer management - now and future: Comparison
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Please note this is a comparison between Version 2 by Peter Tang 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]. 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]. 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]. 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]. 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]. 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], 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

Primary Outcome Studied in the Trial

Top 3 Treatment-Related Adverse Events

Notes
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

Experimental Arm

Clinical Trial Identifier

Treated Cancer Group

Experimental Arm

Comparative Arm

Comparative Arm

Primary Outcome

Primary Outcome

Secondary Outcome (Main)

Secondary Outcome (Main)

First line

III

NCT03875235

[

27]

First line

III

NCT03773302

BTC

FGFR rearrangement

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)

First line

III

NCT04003636

BTC

CCA

Pembrolizumab + GC

Pemigatinib

GC + placebo

GC

Anemia

OS

PFS

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)

PFS, ORR, DOR

OS, OR, DOR, DCR

II

NCT03796429 [36]

BTC

III

II/III

NCT03773302

NCT04066491

FGFR2 fusion/translocation

BTCToripalimab + GC

CCA

PD-1

Infrigatinib

Single arm

PFS—6.7 m

OS—NR

Leukopenia

GC

Anemia

Rash

ORR—21

DCR—85%

G3/4, non-hematological in 20% and hematological—69%

Bintrafusp alfa

PFS

GC + placebo

OS

DLT

PFS, DOR, ORR

OS. DCR, DOR, BOR

II

III

NCT03951597 [37]

NCT04093362

iCCA with FGFR2

II

iCCA

NCT04217954

Toripalimab + lenvatinib + GemOx +

BTC

iCCA

PD-1 + TKI

HAIC (oxaliplatin + 5-FU) + toripalimab (T) + bevacizumab

Futibatinib

None

Single arm

GC

ORR—80% (1CR and three patients obtained enough control to allow for resection)

PFS, ORR

PFS

OS, AE, CA 19-9, DCE-MRI signal change, DWI MRI signal change

Jaundice

Rash

Proteinuria

ORR. DCR. OS. Safety/Tolerability

DCR—93.3%,

PFS—10 m

OS—NR

DOR—9.8 m

II

II

NCT04361331 [38]

iCCA

Lenvatinib + GemOx

NCT03768414

TKI

None

Single arm

ORR—30%

ORR

1/30 was down staged to have resection

Fatigue

Jaundice

II

Not specific

NCT04172402

BTC

Vomiting

BTC

GC/NP

None specified

GC

PFS and OS—NR

OS

PFS, ORR, DCR

DCRc—87%

TS-1 + gemcitabine + nivolumab

No G5, ≥G3 in 40%

Ib

II

II

NCT02992340

II

NCT03579771

NCT03898895

BTC

High risk *

iCCA

Varlitinib + GC

Resectable IHC

Pan-HER 2

Camrelizumab + radiotherapy

GC/NP

Single arm

None

DLT—1/11 (200 mg); 1/12 (300 mg)

blood and lymphatic system disorders

GCSR

PR = 8/23; SD = 12/23

PFS

OS, AE, tumor response

RR, R0; OS; PFS

ORR—35%, DCR—87%, DoR—4 m, PFS—6.8 m

Ib

II

NCT02128282 [

III

39]

NCT03478488

CCA

Silmitasertib (CX-4945) + GC

Casein kinase 2 (CK2)

Subsequent lines

Single arm

k

PFS 11 m

II

Diarrhea

Neutropenia

NCT04722133

Nausea

BTC

HER 2

aBTC

Trastuzumab-pkrb + FOLFOX

None

Compared to GC—Better PFS

Lesser neutropenia

KN035 (PD-L1 antibody) + gemcitabine + oxaliplatin

ORR

PFS, OS, DCR, incidence of TRAE

GEMOX

OS

PFS, ORR, DCR, DOR, TTP

I

NCT02375880 [40]

II

II

jRCT2031180150

NCT03796429

BTC

HER 2

DKN-01 + GC

BTC

Advanced solid tumors #

Dickkopf-1 (DKK1)

Gemcitabine/S-1 + toripalimab

Trastuzumab and pertuzumab

Single arm

None

Safety—no DLT

ORR

Neutropenia

Thrombocytopenia

Leukopenia

None

PFS, OS

PFS, OS, DoR, safety

ORR—21.3%

PFS—8.7 m

ORR, Safety

Subsequent lines

II

III

II

NCT02091141

(My Pathway)

NCT04027764

NCT02989857 (ClarIDHy) [41]

CCA

HER 2

BTC

Ivosidenib (IVO)

BTC #

IDH-1

Trastuzumab and pertuzumab

IVO alone vs.

placebo

None

PFS—2.7 m vs. 1.4 m (HR = 0.37; 95% CI 0.25–0.54;

Toripalimab + S1 and albumin paclitaxel

ORR

p < 0.0001).

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)

None

ORR

PFS, DCR, OS

DCR, PFS, OS, AE

II

NCT02966821 [42]

BTC

II

NCT04466891

Surufatinib

HER 2

BTC

VEGF

Zanidatamab monotherapy

II

NCT04191343

BTC

Single arm

Toripalimab + GEMOX

None

PFS rate at 16 wks—46.33% (95%, 24.38–65.73)

None

ORR

Elevated bilirubin

ORR

Hypertension Proteinuria

PFS—3.7 m

DoR; DoR > 16 wks; DCR, PFS, OS; incidence of TRAE, PK

OS—6.9 m

None specified

II

II

ChiCTR1900022003 [

II

43].

NCT02999672

NCT04300959

BTC

HER 2

BTC

Anlotinib +

sintlimab

TKI + PD-1

CCA #

Anlotinib hydrochloride + PD1 + gemcitabine + cisplatin

Trastuzumab emtansine

Gemcitabine Cisplatin

Single arm

None

OS—NR

OS 1 yr

BOR

OS 2 yr, PFS, ORR, AE

Hypertension **

Diarrhea

Hypothyroidism

PFS, OS, TRAE, SAE, PK

PFS—6.5 m

ORR—40%

DCR—87%

II

II

NCT02052778 [

Subsequent lines

44].

NCT04482309

iCCA #

Futibatinib

II

HER2

FGFR2

BTC #

Trastuzumab deruxtecan

Single arm

ORR 37%

NCT03482102

Hyperphosphatemia

None

Diarrhea *

Dry mouth *

DoR—8.3 m and DCR = 82%

HCC, BTC

ORR

DOR, DCR, PFF, OS, AEs, PK and immunogenicity

Tremelimumab + durvalumab + radiation

II

None

II

NCT03230318 [45]

NCT03839342.

iCCA

Non-V600E BRAF mutations

Derazantinib

Advanced solid tumors

FGFR2—mutations and amplifications

#

Single arm

3-month PFS rate—76%

Bimimetinib + encorafenib

Not specified

None

DCR = 80%

PFS = 7.3 m

6-month PFS rate = 50%

ORR

Safety, DCR, PFS

II

NCT03797326 [46]

BTC #

Pembrolizumab + lenvatinib

PD-1 + TKI

Single arm

ORR

AE, OS, DCR, PFS, DOR, TTP

II

NCT04238637

BTC

Durvalumab (D) vs. D + T

None

ORR

II

NCT02428855

IDH1 mutation

iCCA

Dasatinib

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

II

NCT02265341 [47]

BTC

II

Ponatinib

FGFR2

Single arm

ORR—9%

Lymphopenia, Rash

Fatigue (50%)

CR = 0, PR—8%, SD = 36%. PFS—2.4 m and OS—15.7 m

NCT02675829

HER2 amplification

Advanced solid tumors #

Ado-Trastuzumab emtansine

None

ORR

None

II

NCT03834220 [48]

II

CCA among Solid tumors

Debio 1347

FGFR Fusion

Single arm

ORR—2/5 (40%) of CCA

Fatigue

Hyperphosphatemia

Anemia

DoR and PFS were 16.1 weeks and 18.3 weeks (in all patients), respectively.

Safety, DoR, PFS, OS

II

NCT02821754

HCC, BTC

D + T

D +T + TACE

D + T + RFA

D + T + Cryo

PFS

Safety

NCT03207347

BAP1 and other DDR genes

CCA #

II

NCT02703714

BTC

Pembrolizumab

and sargramostim (GM-CSF)

None

ORR

AE, PD-L1 positivity, PFS, OS, DOR

Niraparib

None

ORR

I/II

NCT03937895

BTC *PFS, OS, TRAE

Allogeneic natural killer cells + pembrolizumab

None

Phase I—DLT

Phase II—ORR

II

TTP, toxicity

II

NCT01953926 [49]

NCT03212274

BTC + AC #

Neratinib

II

IDH1/2 mutation

HER2 or EGFR Exon 18

Single arm

ORR—12%

CCA

Diarrhea *

Vomiting *

Olaprib

PSS—2.8 m

None

OS—5.4 m

ORR

NCT04306367

BTC

Pembrolizumab and olaparib

PFS, OS, safety

mFOLFOX-historical control

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

≥3 Grade TRAE in 28%

ORR—27%

DCR—83%

II

NCT04042831

DNA repair gene mutation

BTC

Olaparib

None

ORR

II

NCT04295317

iCCA—adjuvant

PD-1 blocking antibody SHR-1210 + capecitabine

NoneOS, PFS, TRAE, DoR

PFS

OS, side effects

I

NCT02699515 [51

II

]

NCT03250273

BTC #

Bintrafusp alfa,

TGF-β and PD-L1

BTC, PDA

Single arm

Safety—emergent and all adverse events

Rash

Fever

Increased lipase

63% had TRAE

37% ≥ G3

II

NCT03207347

DNA repair gene mutation

CCA #

Entinostat + nivolumab

Niraparib

NoneNone

ORR

OS, PFS, TRAEs

ORR

Toxicity, PFS, OS, DOR

I

NCT02892123 [52]

BTC #

ZW25 (Zanidatamab)

bispecific HER2

Single arm

Safety/tolerability—only G1–G2 reported in 70%

Fatigue **

Diarrhea

Infusion reaction

ORR—47

DCR—65%

DoR—6.6 m

II

NCT02162914

VEGF mutation

CCA

Regorafenib

None

PFS

RR, OS

II

Ib

NCT03996408 [53]

BTC

Anlotinib

TQB2450

TKI + PDL1

Single arm

DLT/ MTD

in first 3 weeks (one cycle)—none

RP2D—25 mg

ORR—42%

* Hypertension

Leukopenia

Increased total bilirubin

Neutropenia

PFS—240 days

DCR—75%
# 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

NCT02866383

BTC, PDA

Nivolumab + ipilimumab + radiotherapy

Nivolumab + radiotherapy

CBR

AE, ORR, PFS, OS, QOL

II

NCT03339843

II

CDK 4/6 mutation

NCT04057365

BTC

CCA #

DKN-01 + nivolumab

Abemaciclib

None

None

ORR

Anti-tumor activity

PFS, OS, toxicity

PFS, OS

II

NCT04003896

CDK 4/6 mutation

II

NCT03639935

BTC

BTC

Abemaciclib

Rucaparib + nivolumab

None

None

ORR

PFS, DCR, OS, QoL

4-month PFS rate

Response rate, PFS, OS

II

NCT02232633

STAT3 inhibitor

CCA

BBI503

None

DCR

II

NCT04299581

iCCA

Camrelizumab + cryo

ORR, OS, PFS, PK TRAE

None

ORR

DOR, PFS, OS, DCR, AE

II

II

NCT03878095

NCT03999658

IDH1/2 mutation

BTC #

CCA #

STI-3031

anti-PD-L1 antibody

Ceralasertib + olaparib

None

None

ORR

ORRPFS, OS, DoR, Safety

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

I/II

NCT02273739

II

NCT03801083

IDH2 mutation

Advanced solid tumors

BTC

#

Tumor infiltrating lymphocytes (TIL) + aldesleukin

Enasidenib

Enasidenib

None

None

DLT, ECOG

ORR

Plasma concentration metrics

CRR, DOR, DCR, PFS, OS, QOL

I

NCT04764084

HRR mutations

CCA #

Niraparib + anlotinib

I/II

NCT03684811

BTC #

None

FT-2102 vs. FT-2102 + nivolumab

DLT, MTD

ORR, PFS

None

DLT, Dose, ORR

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

I

I/II

NCT04521686

NCT03475953

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

BTC #

CCA #

Regorafenib + avelumab

LY3410738

LY3410738 + GC

  

Maximum tolerated dose

None

ORR

Safety and tolerability

Efficacy

PK properties

I = dose

II = antitumor activity

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

I

NCT02381886

IDH1 mutation

BTC #

IDH305

None

DLT

I/II

NCT03785873

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

BTC

Nal-Irinotecan + nivolumab + 5-Fluorouracil + leucovorin

None

I = DLT

II = PFS

AE, ORR, OS

I

NCT03272464

BRAF-V600E

BTC #

I

NCT03849469

JSI-1187 + dabrafenib

None

iCCA #TRAE

XmAb®22841 and pembrolizumab

DOR, OS, PFS, TTP

XmAb

®

22841 Monotherapy

Safety and tolerability

None

I

NCT04190628

I

BRAF-V600E

NCT03257761

BTC #

ABM-1310 + cobimetinib

None

MTD

TRAE, PK, DOR, OS, PFS, TTP

BTC, PDA, HCC

Guadecitabine + durvalumab

None

AE, Tumor response

OS, PFS

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

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]. 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]. A recently presented pooled analysis of these two trials further proved this point [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 [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) [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 [63][64][65]. The addition of pre-operative radiation can increase the probability of R0 resection in these tumors [66][67]. On the other hand, NAT did not result in any survival advantage in managing resectable BTCs in the reported studies [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 [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 [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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