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Alqahtani et al. Hepatoma Res 2020;6:70 I http://dx.doi.org/10.20517/2394-5079.2020.65 Page 9 of 15

inhibitors of mutant IDH proteins are under clinical evaluation in patients with IDH-mutant solid tumors
(including CCA), e.g., enasidenib (NCT02273739), IDH305 (NCT02381886), and AG-881 (NCT02481154).

Targeting ROS1 and NTRK fusions
[63]
Gene fusions involving ROS1 have been reported in about 8% of CCA patients , and an oncogenic role for
[64]
ROS kinase fusions was established in a CCA mouse model . These findings make ROS1 an interesting
therapeutic target. The ALK and ROS1 inhibitors ceritinib and crizotinib are already being used in patients
with metastatic non-small cell lung cancers that harbor ALK and ROS1 fusions. Phase II studies are
ongoing to investigate their potential in patients with ROS1- and/or ALK-mutated CCA (NCT02374489
and NCT02034981). Recently, the FDA gave an agnostic approval to the NTRK inhibitor larotrectinib to
treat patients with solid tumors harboring an NTRK gene fusion. This approval was based on the results
of three multicenter, single-arm trials (LOXO-TRK-1400, SCOUT, and NAVIGATE) of patients with solid
tumors and an NTRK fusion. Larotrectinib induced an ORR of 75%, with 71% of responses ongoing at
[65]
one year . These studies also included two patients with CCA, one of whom experienced disease
[65]
stabilization under larotrectinib . In August 2019, the FDA approved the NTRK inhibitor entrectinib for
treating patients with solid tumors and NTRK gene fusions. This approval followed an integrated analysis
[66]
of the pivotal Phase II STARTRK-2, Phase I STARTRK-1, and Phase I ALKA-372-001 trials . In these
studies, in which several NTRK-positive advanced CCA were included, entrectinib induced an ORR of 57%,
with a median duration of response of 10 months. Notwithstanding the rarity of NTRK fusions in CCA
patients, the fact that this alteration is now actionable with effective targeted therapies justifies screening
for it in patients with advanced CCA.

EGFR-directed therapy
Patients with CCA often harbor mutations in EGFR . The mutations are more common in patients with
[52]
[67]
pCCA and dCCA (about 15%) than in iCCA patients . EGFR inhibitors in patients with biliary tract
cancer, either as monotherapy or in combination with chemotherapy, have been studied. Unfortunately,
the trials consistently yielded disappointing results [68,69] . The only phase III trial of EGFR inhibitors in this
condition studied the addition of erlotinib to gemcitabine and oxaliplatin as first-line treatment for patients
with metastatic biliary cancer; although the response rate was significantly increased, this did not translate
[70]
into a longer PFS or OS . Similarly, the addition of panitumumab to Cis-Gem did not improve the ORR,
[71]
PFS, or OS in a phase II trial of 62 patients with KRAS-wildtype biliary tract cancer , and no improvement
in ORR or PFS was found in a phase II/III TreeTopp trial that evaluated the addition of the pan-HER
inhibitor varlitinib to capecitabine as a second-line treatment for patients with biliary tract cancer.

Angiogenesis-directed therapy
The results of preclinical studies suggest that several angiogenic factors are important in the tumorigenesis
of biliary tract cancers [72,73] . Thus, angiogenesis-directed therapy has been explored as a therapeutic strategy
in patients with these tumor types. In a phase II trial of 35 patients with advanced biliary tract cancer, the
combination of GEMOX with bevacizumab had promising antitumor activity (median PFS: seven months;
six-month PFS rate: 63%) with a tolerable safety profile . In a randomized phase II trial (n = 57), the
[74]
addition of bevacizumab to GEMOX significantly prolonged the median PFS, from 3.72 to 6.48 months
[75]
(P = 0.049), with only a small increase in toxicity . In contrast with those results, a randomized phase II
trial, presented during the 2020 annual Gastrointestinal Cancers Symposium, found that the addition of the
[76]
VEGF inhibitor ramucirumab did not improve the ORR, PFS, or OS in patients with biliary tract cancer .
Similarly, a phase I study evaluating a combination of ramucirumab and the immune checkpoint inhibitor
[77]
pembrolizumab found a limited clinical effect in patients with previously treated biliary tract cancer .

Emerging targets
Several other promising new drugs are in early clinical development for the treatment of patients with
CCA. Constituted JAK/STAT activation is a recurrent finding in CCA, making it a potential therapeutic