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Page 8 of 21 Yang et al. Hepatoma Res 2023;9:48 https://dx.doi.org/10.20517/2394-5079.2023.68

achieved 35.5% and 7.5 months, respectively, with median progression-free survival (mPFS) of 6.9 months
(95%CI 6.2-9.6) and mOS of 21.1 months (95%CI 14.8- not estimable). Hyperphosphatemia constituted the
[28]
most frequent adverse events (AEs) (all-grade 60% and ≥ grade 3 12%) . The outcomes of cohort A were
found to be better than those of cohort B with other mutations or cohort C with no mutations. The ORR,
mPFS, and mOS were 0, 4.0 months (95%CI 2.3-6.5), and 6.7 months (95%CI 2.1-10.6) in cohort B,
respectively; in cohort C, they were 0, 1.7 months (95%CI 1.3-1.8) and 2.1 months (95%CI 1.2-4.9),
respectively. In the bridging study (CIBI375A201) conducted in China, comparable results were observed
among 30 evaluable subjects harboring FGFR2 fusion/rearrangement with ORR of 50% and mPFS of 6.3
months .
[29]

Futibatinib (TAS-120)
Futibatinib (TAS-120), an irreversible inhibitor of FGFR1-4 with a unique capability of forming covalent
bonding in the ATP pocket of the tyrosine kinase domain, has been recommended as a second-line
[30]
treatment for FGFR2-rearranged iCCA in the NCCN Guidelines (2022) . FOENIX-CCA2, a phase 2
single-arm study, included 103 patients with unresectable or metastatic iCCA of FGFR2 fusions/
rearrangements after previous therapy (excluding FGFR inhibitors). The ORR achieved 41.7%, with mDOR
of 9.7 months (95%CI, 7.6-17.0), mPFS of 9.0 months (95%CI 6.9-13.1), and mOS of 21.7 months (95%CI
14.5- not estimable). Hyperphosphatemia remained the most common AE (all-grade 85% and ≥ grade 3
[7]
30%) .
Infigratinib (BGJ398)
Infigratinib, a selective ATP-competitive inhibitor targeting FGFR1-3, was assessed in a phase 2 single-arm
trial for advanced iCCA with FGFR fusions/rearrangements after first-line gemcitabine-based treatment .
[31]
In cohort one (n = 108), the ORR, mDOR, mPFS, and mOS were 23.1%, 5.0 months, 7.3 months (95%CI
5.6-7.6), and 12.2 months (95%CI 10.7-14.9), respectively. The most frequent treatment-related adverse
events (TRAEs) of any grade were hyperphosphatemia (76.9%). Unfortunately, the phase 3 trial of
infigratinib (NCT03773302) was closed due to the withdrawal of New Drug Application.

Derazantinib (ARQ 087)
Derazantinib, an ATP-competitive inhibitor of FGFR1-3, was evaluated in a phase 2 single-arm trial
F
(FIDES-01) for advanced iCCA with FGFR2 fusions (FGFR2 ) or mutations/amplifications (FGFR2 )
MA
F
[32]
following one or more lines of chemotherapy . FIDES-01 study included 143 patients (103 with FGFR2
and 40 with FGFR2 ). In FGFR2 cohort, the ORR was 21.4%, with mPFS of 8.0 months (95%CI 5.5 - 8.3)
MA
F
MA
and mOS of 17.2 months (95%CI 12.5-22.4). By contrast, in FGFR2 cohort, ORR was only 6.5%, with
mPFS of 8.3 months (95%CI 1.9-16.7) and mOS of 15.9 months (95%CI 8 .4- not estimable). The most
frequent AEs (any grade/ ≥ grade-3) were hyperphosphatemia (37%/3%). Derazantinib demonstrated
significant clinical benefits for iCCA with FGFR2 alterations, including fusions, mutations, and
amplifications.
IDH1/2 mutations
In the citric acid cycle, IDH is one of the crucial rate-limiting enzymes, which catalyzes the oxidative
decarboxylation of isocitrate to generate alpha-ketoglutarate (α-KG), simultaneously producing carbon
dioxide and NADPH/NADH. The IDH family can be divided into two categories according to their
catalytic characteristics. One is NAD -dependent IDH3, which includes α, β, and γ subtypes. The other
+
comprises NADP -dependent IDH1 and IDH2, which category generates NADPH in peroxisomes and
+
cytoplasm (IDH1) or in mitochondria (IDH2). IDH3 mutations are infrequent in iCCA, but IDH1 and
IDH2 mutations can lead to a conversion of α-KG to 2-hydroxyglutarate (2-HG) . Excessive accumulation
[33]