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assessment in prospective investigations. Moreover, other potential therapeutic targets, including isocitrate
dehydrogenase-1 (IDH1) [22,23] , human epidermal growth factor receptor-2 (HER2) [24,25] , and the BRAF proto-
[25]
oncogene (BRAF) , are also being investigated, showing promising outcomes [Figure 1]. A summary of
top mutation targets and corresponding drugs in ICC are listed in Table 1

In this review article, we elegantly delineated a series of targeted drugs that were either proved by the FDA
or still in clinical trials.

Fibroblast growth factor receptor inhibitors
FGFR2 gene variations are prevalent in ICC, with an incidence ranging from 11% to 45% [17,20,26] . Specifically,
FGFR2 rearrangements and aberrations are detected in approximately 15% of ICC cases . In the
[27]
transformative journey from normal cells to tumor cells in ICC, these genetic mutations play an
irreplaceable role by influencing crucial pathways. This impact occurs especially when FGFR2 fusions and
rearrangements affect key pathways, ultimately leading to the transition from normal cells to tumor cells .
[20]
As a result, they have been prospectively assessed and recognized as the targets amenable to intervention .
[20]
This highlights the potential therapeutic significance of targeting FGFR2 gene variations in ICC
management.

Pemigatinib, an FDA-approved selective inhibitor of FGFR2, has demonstrated efficacy in the treatment of
ICC with FGFR2 fusion or rearrangement with local infiltration or distant metastasis. The phase II trial,
FIGHT-202, provided valuable insights into the effectiveness of pemigatinib in advanced-stage ICC
[28]
patients . Among those with FGFR2 fusion or rearrangement, the treatment demonstrated a 37.0%
objective response rate (ORR) and an 82.4% disease control rate (DCR). The median relapse-free survival
(median RFS) and overall survival (OS) were 7.0 months and 17.5 months, respectively, while the median
overall survival (median OS) of treated responders reached 30.1 months. Moreover, another study involving
30 subjects assessed the treatment's efficacy . Among them, 15 patients achieved a partial response (PR),
[29]
resulting in an ORR of 50.0% (95%CI: 31.3-68.7). In addition, it is worth noting that among the 31 patients,
a remarkable DCR of 100% (95%CI: 88.4-100) was achieved, with 15 patients demonstrating stable disease
(SD). The median time to response was 1.4 months (95%CI: 1.3-1.4), although the duration of response
(DOR) remains undetermined. In this study, the median progression-free survival (median PRF) was 6.3
months [95%CI: 4.9-not estimable (NE)]. It is important to mention that out of the total patients, eight
individuals (25.8%) experienced grade 3 or higher treatment-emergent adverse events, with the most
commonly observed adverse events including hyperphosphatemia, hypophosphatasemia, and so on. These
promising findings highlight the significant antitumor activity and positive safety characteristics of
pemigatinib, supporting it as a treatment option for patients of ICC with FGFR2 rearrangements. The
ongoing phase III randomized trial, FIGHT-302, is presently enlisting participants to investigate and
determine the effectiveness of pemigatinib compared to the combination of gemcitabine and cisplatin
chemotherapy. This trial focuses on individuals with unresectable or metastatic ICC harboring FGFR2
fusions or rearrangements, serving as a primary treatment option. The overarching goal is to scrutinize and
[30]
establish the comparative advantages and results of these two distinct treatment modalities .
Infigratinib, another FDA-approved FGFR2 inhibitor, has shown promising results in the treatment of
advanced ICC with FGFR2 genomic aberrations. A prospective cohort study evaluated infigratinib in 108
patients with advanced ICC, where they received infigratinib (BGJ398) [31,32] . In the subset of individuals with
FGFR2 gene fusions or rearrangements (n = 83) in which over half of the patient cohort has received
treatments from two or more therapeutic regimens., the ORR, as assessed through centralized review, stands
at 23%, accompanied by a median PFS of 7.3 months. Utilized as a second-line intervention, the ORR