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Page 4 of 10 Ruff et al. Hepatoma Res 2023;9:37 https://dx.doi.org/10.20517/2394-5079.2023.51

Figure 1. IDH1 and IDH2 mutations causes build up of 2-hydroxygluatrate (2-HG). IDH: isocitrate dehydrogenase; CO : Carbon dioxide;
2
+
NADP : nicotinamide adenine dinucleotide phosphate; NADPH: reduced form of NADP. This figure was re-printed from open access
[20]
reference .
IDH mutations and prognosis in ICCA
Unfortunately, there is little convincing evidence that the presence of an IDH mutation is associated with
prognosis. Wang et al. evaluated 326 patients with resected ICCA and found that IDH mutation was
associated with improved overall survival and longer time to tumor recurrence. Tumor recurrence at 1, 4,
and 7 years in patients with IDH mutations was 10.5%, 45.3%, and 45.3%, respectively, while recurrence
rates in patients with wild-type tumors were 41.7%, 71.5%, and 81.3%, respectively . However, this study
[27]
did not provide information on tumor stage or other therapies given to the cohort. Rizzato et al. evaluated
286 patients with biliary tract cancers and found on multivariable analysis that IDH mutation was associated
with better overall survival . Despite these two studies, there are several more that have not demonstrated
[28]
any association between IDH mutation and prognosis for ICCA. Zhu et al. performed genomic profiling of
200 ICCA tumors and did not find any significant association between IDH mutation and overall
[29]
survival . Several other studies have failed to demonstrate an association between IDH mutation and
prognosis, even when stratified for competing variables [30-33] .

Treatment of IDH-mutated CCA
Ivosidenib
Ivosidenib, also known as AG-120, is an IDH1 inhibitor. It binds mutated IDH1 and locks it in its inactive
conformation, thereby allosterically inhibiting the production of 2-HG . It was previously approved for
[34]
patients with IDH1 mutated acute myeloid leukemia. In a phase I study, ivosidenib monotherapy was tested
in IDH1 mutated solid tumors at multiple centers in the United States and France . Included in this study
[35]
were 73 patients with advanced CCA (65 with ICCA, 8 with ECCA) that had recurred or progressed on
standard therapy. Median progression-free survival (PFS) was 3.8 months, with 6- and 12-month PFS
reported as 40.1% and 21.8%, respectively. Median overall survival (OS) was 13.8 months. This study
demonstrated that ivosidenib is well tolerated in patients with previously treated IDH1 mutated CCA.
Additionally, 13 of the patients in this study had post-treatment tumor samples assessed for Ki-67
proliferation index. A reduction in Ki-67 positive cells was seen in 9 of the 13 patients (69%), with a median
reduction of 22.6% across all 13 patients.

A recent phase III, randomized, double-blind study compared ivosidenib to placebo in patients with
advanced or metastatic IDH1 mutated CCA who have previously received at least one treatment regimen