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Page 8 of 13 Pan et al. Hepatoma Res 2024;10:3 https://dx.doi.org/10.20517/2394-5079.2023.44

Table 3. Research on other actionable targets harboring in ICC
Mutation gene Trial Treatment Phrase Findings
IDH1 ClarIDHy(NCT02989857) AG-120 Ivosidenib III ORR: 2.4% vs. 0
vs. placebo median PFS: 2.7 months vs. 1.4 months,
P < 0.0001
median OS: 10.8 months vs. 9.7 months,
HR = 0.69, 95%CI: 0.44 to 1.10, P = 0.060
BRAF ROAR(NCT02034110) Dabrafenib II ORR: 51%
6-month RRS: 63% (95%CI: 47% to 76%)
12-month OS: 56% (95%CI: 38% to 71%)
median OS: 14 months (95%CI: 10 to 33)
HER2 DPT02 (NCT04482309) Trastuzumab deruxtecan (T-DXd) II HER2-positive:
ORR: 36.4% (90%CI: 19.6% to 56.1%)
DCR: 81.8% (95%CI: 59.7% to 94.8%)
median PFS: 4.4 months (95%CI: 2.8 to 8.3)
median OS: 7.1 months (95%CI: 4.7 to 14.6)
HER2-low expression:
ORR: 12.5% (1/8) (95%CI: 0.3% to 52.7%)
DCR: 75.0% (95%CI: 34.9% to 96.8%)
median PFS: 4.2 months (95%CI: 1.3 to 6.2)
median OS: 8.9 months (95%CI: 3.0 to 12.8)
NTRK STARTRK-1(NCT02097810) Entrectinib I ORR = 57% (95%CI 43.2%~70.8%)
median RFS 11.2 mouths (95%CI: 8.0 to 14.9)
median OS 21.0 mouths (95%CI: 14.9 to NE)

DISCUSSION
Writing this review, we addressed certain key targets, target-related medications, and drug-related clinical
studies in ICC, and provided an outlook in the field along with a critical analysis of its limitations. In the
contemporary era, there have been significant changes in the therapy landscape for advanced-stage ICC
with the emergence of mutation-based therapy. Drugs such as pemigatinib and futibatinib have shown
enhanced OS in comparison to conventional chemotherapeutic treatments in ICC patients who have
received prior treatment, with a median OS of approximately 20 months . Additionally, there is a
[30]
promising outlook for the combined utilization of mutation-targeted therapy and immunotherapy .
[39]
Immunotherapy, particularly immune checkpoint inhibitors, has shown remarkable success in ICC by
exploiting the immune system's ability to recognize and attack cancer cells . Despite this, further
[63]
investigation and clinical trials are needed to explore the potential benefits and safety considerations of this
combined strategy, which might offer new hope for patients.

Mutation-based therapy in ICC holds promising treatment prospects, but it also presents numerous
challenges and limitations. In the first place, clinical trials in the field of mutation-based therapy may
encounter various challenges. The rarity of these alterations poses difficulty in identifying eligible patients
for recruitment [9,42,43] . Moreover, there is competition among trials for recruiting patients with FGFR2
alterations, further complicating the enrollment process. Additionally, the outdated practice of using
chemotherapy alone as a comparative arm in trials may limit the ability to accurately assess the efficacy of
FGFR inhibitors. Furthermore, detecting genomic alterations, especially in cases where tissue samples are
limited, can be challenging.

To address these challenges, it is essential to implement strategies that enhance patient recruitment and
improve the accessibility of sequencing methods. This can be achieved by integrating increased dynamism
and decentralization into recruitment and examination. One promising approach is the utilization of
circulating cell-free tumor DNA (ctDNA) analysis [64,65] . This method offers an alternative means of
identifying and detecting genetic modifications, especially in cases where tissue samples are scarce. Ongoing
studies are actively investigating the use of ctDNA as a diagnostic tool, although certain platforms still have