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It provides a concise overview of the trials, medications, and effectiveness associated with the currently
available FGFR inhibitors in Table 2.

Isocitrate dehydrogenase inhibitors
IDH1 mutations have been identified in a subset of ICC cases, estimated to be approximately 15%-20% of
[37]
cases . These mutations result in the production of abnormal IDH enzymes that convert isocitrate to an
abnormal metabolite, 2-hydroxyglutarate (2-HG), which accumulates in cancer cells and contributes to
tumor growth and progression [38,39] .

Ivosidenib, a small-molecule inhibitor targeting IDH1 mutant protein, has demonstrated favorable safety
and long-term disease stability in patients with ICC [22,40,41] . In 2021, it received approval from the US FDA as
a second-line treatment for cholangiocarcinoma patients with local infiltration or distant metastasis who
harbor IDH1 mutation. The results of the ClarIDHy trial revealed that the median RFS was 2.7 months in
[41]
the ivosidenib group compared to 1.4 months in the placebo group . The ORR was 2.4%, with 50.8% of
patients experiencing disease stabilization. Additionally, the median OS among patients treated with
ivosidenib group was 10.3 months, while it was 7.5 months in the placebo group. In the study, ivosidenib
showed a substantial enhancement in PFS compared to placebo, with a PFS of 2.7 months versus 1.4
months, respectively. The hazard ratio was 0.37, indicating a significant reduction in the risk of progression
with the P-value, calculated one-sided, less than 0.0001. In a word, the findings revealed that ivosidenib was
relatively well-tolerated, and targeting IDH1 mutations in advanced ICC offers notable clinical benefits.

Human epidermal growth factor receptor-2 inhibitors
In contrast to extrahepatic cholangiocarcinoma (ECC), ICC has relatively few mutations in HER2, only 5%-
10% [42,43] . Previous studies conducted on ICC patients using lapatinib and varlitinib against HER2 did not
produce noteworthy outcomes [44,45] . Nevertheless, it is crucial to emphasize that the lack of HER2 assessment
in either drug may have contributed to this outcome. In particular, within pre-selected instances of
advanced cholangiocarcinoma exhibiting HER2 genetic modifications, there have been indications of
enhanced outcomes.

[25]
Neratinib underwent assessment in the SUMMIT trial, which involves diverse histological types . Among
the nineteen participants with HER2 mutations who were administered the medication, the median OS was
measured in individuals who had previously undergone at least one round of systematic therapy. The
observed ORR stood at 10.5%, with a median PFS of 1.8 months.

Additionally, several monoclonal antibody agents targeting HER2 were examined in forward-looking study
groups. The amalgamation of trastuzumab and pertuzumab was appraised in the phase II research initiative
[24]
known as MyPathway . Among the 39 patients with HER2-positive biliary cancer (amplified or
overexpressed HER2), nine achieved PR, with an ORR of 23%.

Zanidatamab, a dual-targeting antibody against HER2, was studied in a phase I trial involving 83 patients
with tumors exhibiting HER2 amplification, including 22 patients with HER2-expressed biliary tract
carcinoma (BTC) . The ORR reached 37% in this study, and there were no deaths attributed to the
[46]
treatment.

Another experimental medication, trastuzumab deruxtecan (DS-8201), was assessed in the HERB trial .
[47]
Among the 22 BTC patients who tested positive for HER2, the ORR was recorded as 36.4%. Furthermore,
the DCR was 81.8%, and the median PFS was 5.1 months, with an OS of 7.1 months.