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PROMISING THERAPEUTIC TARGETS IN ICCA
In the past two decades, a multitude of agents targeting VEGF or EGFR in unselected advanced biliary tract
cancer (BTC) have not shown meaningful activity. In iCCA, only limited data of anti-VEGF suggest more
activity in phase 2 second-line setting with a small sample size. To date, FGFR2 fusion or rearrangement,
IDH1/2 mutation, BRAF V600E mutation, RET fusion, NTRK fusion, and ERBB2 amplification or
overexpression have been well studied as therapeutic targets for advanced iCCA [Table 2], although these
aberrant genes are less frequent except FGFR and IDH.

FGFR alterations
FGFR1-5 belong to the transmembrane receptor tyrosine kinase (RTK) family and are high-affinity
receptors for fibroblast growth factors (FGFs). The binding of FGF to inactive monomeric FGFRs triggers a
conformational change in FGFRs, leading to the dimerization and activation of cytoplasmic tyrosine kinases
by phosphorylating tyrosine residues within the cytoplasmic tails of FGFRs, which initiates a cascade of
intracellular phosphorylation, signal transduction, and gene transcription . FGFR1-4 are composed of
[25]
extracellular regions, hydrophobic transmembrane regions, and intracellular tyrosine kinase domains. Their
signaling axis relates to various physiological processes, including cell proliferation, differentiation, tissue
[26]
repair, and angiogenesis . The FGFR-activated signal transduction pathways, including JAK-STAT, RAS-
BRAF-MEK-ERK, and PI3K-AKT-mTOR, are involved in cell proliferation, differentiation, and survival.
The FGF/FGFR pathway is abnormally regulated through three mechanisms: (a) protein overexpression
resulting from FGFR gene amplification; (b) activating mutations that typically enhance ligand affinity,
receptor dimerization and activation (without ligand), or constitutive kinase domain activation; (c) gene
fusion caused by chromosomal translocation.

Common FGFR mutations include gene amplification, activating mutations, gene fusions, and
rearrangements, kinase domain duplications and autocrine activation. An NGS study of 4,853 cases across
various solid tumors showed that FGFR dysfunction was present in 7.1% of tumor samples. FGFR1-4
amplification accounted for 3.5%, 1.5%, 2.0%, and 0.5% of the patients, respectively . FGFR2
[27]
rearrangements or fusions have been reported in iCCA with an incidence of 8%-13% [8-13] . A retrospective
sequencing analysis of 6130 cases of iCCA showed that the incidence of FGFR2 aberrations was 11.2%,
including rearrangements (9.4%), short variants (2.2%), and copy number variations (0.46%). The most
common fusion partners were BiCCA1, FGFR2-N/A, SORBS1, AHCYL1, and CCDC6 .
[8]
The emergence of oncogenic FGFR2 fusion protein presents a promising opportunity for the development
of targeted therapy. Pemigatinib, futibatinib, infigratinib, derazantinib, gunagratinib, aprutumab ixadotin,
and ponatinib have emerged as promising candidates in phase 1 or 2 clinical trials for cholangiocarcinoma
harboring FGFR2 fusion/rearrangement. Phase 3 trials evaluating the efficacy of pemigatinib
(NCT03656536) and futibatinib (NCT04093362) are poised to challenge GEMCIS in the first-line treatment
of cholangiocarcinoma [Supplementary Table 1].

Pemigatinib
Pemigatinib, a small molecule reversible inhibitor of FGFR1-3, has gained approval as the first targeted
therapy for patients with cholangiocarcinoma carrying FGFR2 fusions or rearrangements in subsequent-line
[6]
settings due to the studies of FIGHT-202 and CIBI375A201 . FIGHT-202, a phase 2, open-label and single-
arm study, enrolled 146 patients with metastatic or advanced cholangiocarcinoma who experienced
progression following first-line or subsequent treatments and were relocated into three cohorts: cohort A,
[28]
FGFR2 fusion or rearrangement; cohort B, other mutations on FGFR; and cohort C, no mutations on
FGFR. In cohort A (n = 107), the objective response rate (ORR) and median duration of response (mDOR)