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possible for 23 of these patients (68%), and 18 (53%) have received matched treatment. Among them, the
ORR was 33%, and the DCR was 88%, while a PFS ≥ 6 months was observed in 37%. These patients had a
lower risk for death as compared to the 20 patients not orientated to a matched treatment (mOS 17 months
[73]
vs. 5 months; HR = 0.29; 95%CI: 0.11-0.76; P = 0.008) .

This analysis highlighted the relevance of histology-agnostic personalised medicine in the identification of
patient subgroups to be matched with compounds targeting the specific molecular alteration and paved the
way for the next-generation personalised medicine programs in BTCs.

Several compounds targeting single gene alterations have shown clinical activity and efficacy in advanced
BTCs [Figure 2], others are currently under clinical investigation [Table 3], and many others are on the
horizon [Figure 2].

Currently, the most promising and clinically relevant target therapies are IDH inhibitors for patients
carrying IDH-mutations and compounds targeting FGFR2 gene fusions . Several IDH inhibitors are being
[48]
explored for the treatment of advanced iCCA: inhibitors of IDH1 (ivosidenib), IDH2 (AG221), and pan-
IDH1/2 (AG881). Ivosidenib showed encouraging results in a phase I dose escalation and expansion basket
study. A total of 77 IDH1 mutant patients with refractory iCCA received the IDH1 inhibitor with stable
disease and partial response achieved in 40 and 4 patients, respectively . The positive results were
[74]
subsequently confirmed in the ClarIDHy phase III trial, where 185 patients with IDH1-mutant CCA were
randomised to receive the IDH1 inhibitor ivosidenib or placebo after 1-2 lines of unsuccessful systemic
therapy. Ivosidenib significantly improved PFS (the primary endpoint). mPFS was 2.7 months in the
experimental group and 1.4 months in the placebo group (HR = 0.37; 95%CI: 0.25-0.54; P < 0.001), with a 12
months PFS rate of 22% vs. 0% . The intention to treat analysis showed a mOS of 10.3 months in patients
[10]
treated with ivosidenib vs. 7.5 months in the placebo group (HR = 0.79; 95%CI: 0.56-1.12; P = 0.093) .
[75]
However, the design of the study allowed crossover to ivosidenib in the placebo arm at progression resulting
in 35 patients receiving the experimental drug in the control group. A rank preserving structural failure
time-adjusted analysis taking into consideration the effects of the crossover showed a more clinically
[75]
meaningful result with a 4-months increase in median OS (10.3 months vs. 5.1 months; P = 0.0008) . On
the basis of this trial, ivosidenib has been recently approved by the Food and Drug Administration (FDA)
for adult patients with previously treated, locally advanced or metastatic IDH1-mutated iCCA, which
represent around 13% of all CCA .
[76]
Multiple inhibitors of FGFR isoforms 1-3 have shown activity in phase I/II clinical trials of advanced, pre-
treated, CCA with FGFR2 translocations, including several ATP-competitive, reversible inhibitors
(erdafitinib, infigratinib, pemigatinib, and derazantinib) and non-ATP competitive, covalent inhibitor
[24]
(futibatinib) . The pan FGFR inhibitors BGJ398/infigratinib and ARQ087/Derazantinib showed
meaningful clinical benefits in chemorefractory iCCA patients carrying FGFR2 fusions in a phase II trial,
with tumour stabilisation or regression achieved in the majority of patients. The ORR was 18.8% and 20.7%,
respectively, and DCR 83.3% and 82.8% [77,78] . Infigratinib has recently received FDA approval for the
treatment of chemoresistant FGFR2 rearranged CCA. The FIGHT-202 study investigated the FGFR1-3
inhibitor pemigatinib in 107 pre-treated CCA patients with FGFR2 fusions, obtaining an impressive 37%
ORR, with a median duration of response of 8.1 months, PFS of 7.0 months and mOS of 17.5 months [14,79] .
No activity was recorded for pemigatinib in tumours harbouring mutations of FGFR2, making this
approach specifically for the 10% of CCA with FGFR2 genomic rearrangements. Despite the exciting result
of the FIGHT-202 trial, the enthusiasm is slightly hampered by the single-arm design of the trial, which
lacks randomisation. Nonetheless, FDA and the European Medicines Evaluation Agency have approved