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Ruff et al. Hepatoma Res 2023;9:37 https://dx.doi.org/10.20517/2394-5079.2023.51 Page 7 of 10

Table 1. Selected ongoing clinical trials for IDH-mutated cholangiocarcinoma
Study Clinical trial
Agent Mechanism Condition
phase identifier
Olaparib PARP Inhibitor IDH1 or IDH2 mutated, advanced glioma, Phase II NCT03212274
cholangiocarcinoma, or solid tumors
Olaparib and durvalumab Olaparib: PARP IDH-mutated glioma or cholangiocarcinoma Phase II NCT03991832
Inhibitor
Durvalumab: PD-L1
inhibitor
Olaparib and ceralasertib Olaparib: PARP IDH1 and IDH2 mutated cholangiocarcinoma and Phase II NCT03878095
inhibitor other solid tumors
Ceralasertib: ATR
inhibitor
LY3410738 IDH1 Inhibitor IDH1 R132 mutated solid tumors (including Phase I NCT04521686
cholangiocarcinoma)
Dasatinib Multi-tyrosine kinase IDH-mutated advanced intrahepatic Phase II NCT02428855
inhibitor cholangiocarcinoma
Ivosidenib and nivolumab Ivosidenib: IDH1 IDH1 mutated gliomas and advanced solid tumors Phase II NCT04056910
inhibitor (including cholangiocarcinoma)
Nivolumab: PD-1
inhibitor
Ivosidenib or pemigatinib with Ivosidenib: IDH1 IDH1 mutated or FGFR2 gene aberration Phase I NCT04088188
gemcitabine/cisplatin Inhibitor cholangiocarcinoma
Pemigatinib: FGFR
inhibitor
FT-2102 (Olutasidenib) IDH1 Inhibitor IDH1 mutated glioma or advanced solid tumors Phase I/II NCT03684811
(including cholangiocarcinoma)

ATR: ataxia telangiectasia and Rad3; PARP: Poly-ADP ribose polymerase; IDH: isocitrate dehydrogenase; PD-L1: programmed death ligand 1; PD-1:
programmed death 1.

IDH inhibitor resistance in CCA
The data on CCA IDH inhibitor resistance is more limited. Thirty-seven of the patients who progressed on
ivosidenib in the phase I trial had paired pre-treatment and post-progression biopsies taken for next-
generation sequencing. Of these patients, six had new oncogenic mutations develop at an allele frequency of
5%. Four patients developed co-mutations in the TP53, ARID1A, POLE, PIK3R1, and/or TBX3 genes. One
patient with a stable disease prior to progression developed a new IDH1 mutation by converting the R132C
allele to an R132F. A second patient who initially had a partial response developed an activating IDH2
mutation . This demonstrates two different mechanisms of resistance. First, similar to other cancers, a
[35]
change in the IDH1 mutation or gain of IDH2 mutation can promote acquired resistance. Second, the
presence of new co-mutations in non-IDH genes may also contribute to secondary resistance.

[34]
Cleary et al. described two patients with IDH1 mutated CCA with secondary resistance to ivosidenib . One
patient acquired an IDH2 mutation and the other developed a secondary IDH1 mutation. Even though the
production of 2-HG is less efficient with the double-mutated IDH1 (R132H/D279N versus R132H), the
binding site on the enzyme for ivosidenib is changed. Through an in vitro study, Cleary et al. demonstrated
that the double-mutated IDH1 was resistant to ivosidenib. This study also demonstrated in the lab that
LY3410738 can successfully bind and inhibit the double-mutated IDH1 enzyme .
[34]
What these studies demonstrate is that through either pre-existing or new mutations, the tumor is able to
maintain elevated 2-HG levels and continue to prevent cell differentiation and drive proliferation.
Appropriately identifying co-mutations that confer primary resistance and understanding the underlying
mechanism for why these co-mutations result in resistance may elucidate new potential therapeutic targets.
Additionally, it will allow clinicians to better select patients who will respond to IDH inhibitor therapy. To