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Page 16 of 23 Thonglert et al. Hepatoma Res 2023;9:40 https://dx.doi.org/10.20517/2394-5079.2023.47

FGFR2 fusion or rearrangement
FGFR is a tyrosine kinase receptor that activates several downstream signaling cascades, leading to cell
proliferation. The fusion of FGFR2 results in constitutively active growth factor pathway signaling,
promoting tumorigenesis. FGFR2 fusions occur approximately in 20% of iCCAs and are rare in other
subsites . Phase II single-arm studies showed that FGFR inhibitors, including pemigatinib, infigratinib and
[77]
futibatinib, in patients with previously treated, unresectable locally advanced, or metastatic CCA with
FGFR2 fusion or other rearrangements, have shown an objective response rate (ORR) of 23.1%-42% and a
median PFS of 6.9-9.0 months [78-80] .

Data on the effects of FGFR2 fusion on response to radiotherapy, either alone or in combination with an
FGFR inhibitor for iCCA, remain limited. Few indirect studies have suggested a potential association
between FGFR fusion and radioresistance. Ahmed et al. study demonstrated that FGFR4 mutation inhibited
radiation response in colorectal cell lines, and blocking FGFR-4 signaling with FGFR inhibitor increased
[81]
radiosensitivity . Similarly, Nuryadi et al. also found amplification of FGFR2 in radiotherapy-resistant
cervical cancer . Yoshimoto et al. found that patients with FGFR-mutation-positive cervical cancer treated
[82]
with definitive radiotherapy had significantly worse 5-year PFS compared to FGFR mutation-negative
patients (43.9% vs. 68.5%, respectively; P = 0.010) .
[83]

FGFR inhibitors may potentially increase radiosensitivity. However, the data are limited, and the results are
still conflicting. Ader et al. found that an inhibiting FGF-2 pathway by targeting FGFR increased the
radiosensitivity of human glioblastoma cells in a preclinical study . In contrast, Verstraete et al. found that
[84]
FGFR inhibitors did not result in radiosensitization in colorectal cancer cell lines with high expression of
FGFR2 either in vitro or in vivo .
[85]

Currently, there are no available data on FGFR inhibition and RT for iCCA; more research in this area is
needed. A phase II study (NCT05565794) investigating the combination of SBRT and pemigatinib in locally
advanced iCCA with FGFR fusion or rearrangements is ongoing.

IDH1 mutation
Isocitrate dehydrogenase (IDH) 1 mutation has been observed in approximately 13% of patients with iCCA,
with varying frequency and a higher prevalence in non-Asian (less liver fluke-associated) treatment centers.
[86]
Similar to the FGFR2 fusion, IDH1 mutations are rarely found in eCCA . IDH1 mutation results in the
production of the onco-metabolite 2-hydroxyglutarate (2-HG). The accumulation of 2-HG impairs cellular
differentiation, leading to tumorigenesis . Ivosidenib, an IDH-1 inhibitor, has been approved by the Food
[87]
and Drug Administration (FDA) for adults with previously treated, locally advanced, or metastatic CCA
with IDH1 mutation. This approval was based on the phase III trial 'ClarIDHy', which involved 185 patients
with previously treated advanced IDH1-mutant CCA, comparing ivosidenib with placebo. The study
showed a significant increase in the median PFS from 1.4 months using a placebo to 2.7 months with
ivosidenib treatment (HR 0.37, 95% CI: 0.25-0.54, P < 0.001) .
[88]
Most data on radiation response in patients with IDH mutations come from glioma studies, which have
shown that IDH1/2 mutant tumors exhibit a better response to radiation . There has been only one
[89]
preclinical study for iCCA from Wang et al. The study found that IDH mutant iCCA was more sensitive to
radiation, both in vitro and preclinical animal models, compared to IDH wild-type . Additionally, the
[90]
combination of RT and PARP inhibitors (PARPi) in IDH-mutant iCCA led to significantly delayed tumor
growth compared to radiotherapy alone. Further clinical investigations are warranted to determine the
effect of IDH mutations on radiotherapy response and how radiation can be combined with IDH inhibitors.