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Pan et al. Hepatoma Res 2024;10:3 https://dx.doi.org/10.20517/2394-5079.2023.44 Page 9 of 13

[65]
limitations in detecting specific fusion events .

On another front, the emergence of drug resistance poses a significant challenge in the mutation-based
therapy of ICC [66-68] . For FGFR2 inhibitors, several mechanisms of drug resistance have been recognized,
[67]
with gatekeeper mutations as a prominent example . These mutations sustain FGFR pathway signaling
and confer resistance to currently available inhibitors. On the other hand, studies primarily focused on
acute myeloid leukemia (AML) have revealed receptor tyrosine kinase (RTK) pathway genes as a cause of
resistance against IDH1 inhibitors . However, the mechanism of resistance in IDH mutations in ICC
[69]
requires further investigation.

By gaining a comprehensive understanding of these mechanisms, novel strategies can be developed to
overcome resistance and improve patient outcomes. This may involve the development of new drugs,
combination therapies, or alternative treatment approaches tailored to the specific resistance mechanisms
identified. The ultimate goal is to maximize the benefits of targeted therapies and optimize their long-term
effectiveness in the management of ICC.

The integration of immunotherapy with chemotherapy has emerged as a recent focal point in ICC. In a
phase II trial, the investigational combination of nivolumab, gemcitabine, and cisplatin exhibited
compelling effectiveness and well-tolerated safety in 32 patients . The cohort included individuals resistant
[70]
to gemcitabine or cisplatin and chemotherapy-naive patients. Encouragingly, the regimen achieved a
noteworthy 55.6% ORR, with 18.6% CR, showcasing notable efficacy even in cases resistant to conventional
chemotherapy. The DCR reached an impressive 92.6%. For cohort A, where patients were resistant to
standard chemotherapy, one achieved a CR, and one achieved a PR. In the chemotherapy-naive cohort B,
61.9% attained an OR. The median PFS for all patients (cohorts A+B) was a robust 6.1 months, and the
median (OS) stood at 8.5 months, accompanied by a notable 33.3% 12-month OS rate. Noteworthy adverse
events included thrombocytopenia (56%) and neutropenia (22%). These comprehensive findings underscore
the promising potential of nivolumab combined with GEMCIS as an effective and tolerable therapeutic
approach for patients with advanced BTC, especially in cases resistant to traditional chemotherapy. Despite
promising outcomes in the 32-patient cohort, the relatively modest sample size and a median follow-up of
12.8 months may pose challenges in extrapolating findings to a broader patient spectrum and
understanding potential long-term implications. While these findings are encouraging, careful
consideration of these limitations underscores the need for future well-controlled studies to substantiate
and refine these preliminary observations.

Presently, the realm of new adjuvant and adjunct therapies for ICC lacks involvement in clinical studies
with mutation-based targeted treatment [71,72] . This absence can be attributed to two primary factors. Firstly,
there is an absence of small-molecule targeted drugs that have transitioned into the forefront of treating
unresectable ICC. Unlike chemotherapy approaches like GEMCIS, targeted therapies typically come into
play after the establishment of a molecular diagnosis. While clinical trials have investigated the
responsiveness of unidentified ICC subtypes to HER2-targeted drugs, the limited patient enrollment and
scarcity of associated research impede the widespread acceptance of these treatments as primary therapies.
Secondly, the significance of postoperative adjuvant therapy in preventing recurrence introduces the
consideration that genetic mutations recurring from primary ICC may have undergone substantial changes.
In essence, gene mutation types initially identified through surgical specimens may no longer manifest in
recurrent tumors. Instead, these tumors might rely on different gene mutations for progression. This
assumption implies that targeted therapy based on prior genetic testing results would lose its specificity.
Despite explorations into the molecular subtypes of ICC, a universally accepted viewpoint remains elusive,