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Page 8 of 15 Alqahtani et al. Hepatoma Res 2020;6:70 I http://dx.doi.org/10.20517/2394-5079.2020.65

60.6% of patients experienced disease stabilization under therapy, for an overall disease control rate of
75.4% (83.3% in FGFR2-fusion/rearrangement patients). The estimated median PFS in this study was
5.8 months. Grade ≥ 3 AEs occurred in 41% of patients, with hyperphosphatemia (16.4%), stomatitis (6.6%),
[56]
and palmar-plantar erythrodysesthesia (4.9%) being the most common high-grade toxicities . A phase III
clinical trial comparing infigratinib to Gem-Cis in the first-line treatment of patients with locally advanced/
metastatic CCA and an FGFR2-fusion/rearrangement is ongoing (NCT03773302).

During the 2020 annual meeting of the American Society of Clinical Oncology (ASCO), phase II data
[57]
were presented for the irreversible FGFR1-4 inhibitor futibatinib . In total, 103 patients with unresectable
or metastatic iCCA and an FGFR2 fusion (or another rearrangement involving this gene) with disease
progression after at least one prior systemic therapy (including Gem-Cis) were treated with futibatinib at
a dose of 20 mg/day. The data presented at ASCO included the first 67 patients with at least six months of
follow-up. An objective response was obtained in 37.3% of patients, with an additional 44.8% of patients
experiencing disease stabilization (disease control rate 82.1%). Responses also proved to be durable, with
a median duration of response of 8.3 months. The median PFS was reported at 7.2 months, with a 6- and
12-month PFS rates of 61.0% and 39.4%, respectively. Grade ≥ 3 AEs were reported in 56.7% of patients,
with 10.4% of treatment-related severe AEs. Only one patient had to discontinue the therapy for reasons of
[57]
toxicity. The most common Grade 3 AE with futibatinib consisted of hyperphosphatemia (26.9%) . Based
on these excellent results, futibatinib is also being compared to Gem-Cis in a randomized phase III trial,
including previously untreated CCA patients (NCT04093362).

In other work, the pan-FGFR inhibitor erdafitinib demonstrated clinical activity in patients with FGFR-
mutated solid tumors. In a phase I basket trial, erdafitinib induced a partial response in 3 of 11 CCA
patients with an FGFR2-fusion or rearrangement .
[58]

A fifth pan-FGFR inhibitor that demonstrated potential in patients with CCA is derazantinib. In a
multicenter phase I/II trial of 29 patients with unresectable iCCA and an FGFR2-fusion, it was associated
with an ORR of 20.7% and a disease control rate of 82.8%. The estimated PFS was 5.7 months, and
[59]
27.6% of patients had Grade ≥ 3 AEs . A pivotal trial of derazantinib in patients with iCCA is ongoing
(NCT03230318).

IDH-directed therapy
Mutations in IDH-1 and -2 are present in 15-20% of patients with iCCA [51,60] . These mutations profoundly
[61]
affect cell differentiation and cell growth, and they are involved in tumorigenesis . Several inhibitors of
mutant IDH proteins have been developed in recent years. Ivosidenib (AG-120) is a first-in-class, oral,
small-molecule inhibitor of the mutant IDH1 protein. In the randomized, phase III ClarIDHy trial, 185
previously treated patients with advanced CCA and an IDH1 mutation were randomly assigned (2:1) to
receive either ivosidenib (500 mg per day) or matching placebo . The study met its primary endpoint,
[62]
with a significantly longer median PFS for patients in the ivosidenib arm than in the placebo arm
(2.7 months vs. 1.4 months; HR = 0.37, 95%CI: 0.25-0.54, P < 0.001). At the 6- and 12-month marks, 32%
and 21.9% of patients, respectively, treated with ivosidenib were free of progression, whereas none of the
patients in the placebo arm was progression-free at six months. The ORR with ivosidenib was low (2.4%),
with 50.8% of patients having disease stabilization. The median OS among patients treated with ivosidenib
was 10.8 months. Patients in the placebo arm had a median OS of 9.7 months, but this OS was significantly
influenced by 57% of placebo patients crossing over to ivosidenib. Overall, 46% of patients experienced
a Grade 3/4 AE on ivosidenib as compared with 36% with placebo; the most common AEs seen with
[62]
ivosidenib were nausea (32.1%), diarrhea (28.8%), and fatigue (23.7%) . The results of phase III ClarIDHy
trial are especially important in CCA treatment as they provide level A evidence for the efficacy of targeted
therapy in this setting and establish a role for molecular profiling in this cancer type. Several other