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.
# 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

II

NCT04003896

CDK 4/6 mutation

BTC

Abemaciclib

II

None

NCT03639935

BTC

Rucaparib + nivolumab

None

4-month PFS rate

ORR

PFS, DCR, OS, QoL

Response rate, PFS, OS

II

II

NCT02232633

NCT04299581

STAT3 inhibitor

iCCACCA

BBI503

None

Camrelizumab + cryo

None

ORR

DCR

DOR, PFS, OS, DCR, AE

ORR, OS, PFS, PK TRAE

II

NCT03878095

II

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 #

II

Enasidenib

Enasidenib

None

DLT, ECOG

Plasma concentration metrics

NCT03801083

BTC

Tumor infiltrating lymphocytes (TIL) + aldesleukin

None

ORR

CRR, DOR, DCR, PFS, OS, QOL

I

I/II

NCT04764084

NCT03684811

HRR mutations

BTC #

CCA #

FT-2102 vs. FT-2102 + nivolumab

Niraparib + anlotinib

None

None

DLT, MTD

ORR, PFS

DLT, Dose, ORR

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

I

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

I

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

I

I

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

I

NCT04190628

I

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

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

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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