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Alqahtani et al. Hepatoma Res 2020;6:70 I http://dx.doi.org/10.20517/2394-5079.2020.65 Page 7 of 15

arm was 50.6% and 25.9%, respectively, compared with 5.5% and 11.4% for active symptom control alone.
mFOLFOX was well tolerated, with only a manageable increase in the rate of Grade ≥ 3 neutropenia and
[47]
fatigue .
The most prominent alternative for mFOLFOX in second-line treatment is a combination of irinotecan and
2
2
capecitabine (XELIRI). The XELIRI regimen (irinotecan 180 mg/m on Day 1 and capecitabine 1000 mg/m
BID on Days 1-10 of 14-day cycles) was compared to irinotecan alone in a phase II trial that had 60 patients
with Gem-Cis pretreated biliary tract cancer . In that trial, XELIRI doubled the nine-month OS rate from
[48]
32% to 60.9% (no significant difference in median OS: 10.1 months vs. 7.3 months; P = 0.107) and increased
the disease control rate from 50% to 63.3%. This benefit came at the cost of only a modest increase in
[48]
toxicity, but there was a higher rate of palmar-plantar erythrodysesthesia with XELIRI (6.7% vs. 0%) .

A third option for advanced CCA patients who failed first-line Gem-Cis is 5-FU-based therapy.
Unfortunately, there are no randomized data for comparison of 5-FU to FOLFOX or XELIRI for this
[49]
indication. The best data come from a large retrospective series of 321 advanced CCA patients . In that
series, 5-FU-based chemotherapy was modestly effective as second-line chemotherapy for patients with
advanced biliary tract cancer who failed on first-line Gem-Cis (ORR 8% for 5-FU platinum combinations
and 1% for 5-FU alone). A 5-FU-platinum combination was not associated with a better OS or PFS than
[49]
those outcomes with 5-FU monotherapy .
Molecularly targeted therapy for CCA
[50]
CCA has a high level of intra- and intertumoral heterogeneity . As a result, clinical trials testing
molecularly targeted agents in unselected patients with CCA have consistently yielded negative results.
In recent years, however, advances in whole-exome and transcriptome sequencing have shed light on the
[51]
genetic landscape of the CCA subtypes, opening the door to tailored treatment approaches . In fact,
recent biomarker-driven clinical trials in CCA patients have reported positive outcomes. These results have
prompted FDA approval of pemigatinib as the first targeted treatment for patients with previously treated,
advanced CCA who harbor an FGFR2-fusion or rearrangement. We now present an overview of the
molecularly targeted agents that are under clinical evaluation in CCA patients.

FGFR-directed therapy
Gene fusions involving FGFR2 have been reported in 10-20% of iCCA patients [52,53] . The fusions result
in constitutive activation of FGFR2, ultimately leading to activation of oncogenesis-promoting signaling
[54]
pathways, such as RAS-RAF-MEK . Several FGFR-targeting agents have been evaluated for the treatment
of advanced CCA. As indicated above, pemigatinib recently became the first FDA-approved molecularly
targeted agent for treating patients with CCA, specifically those with previously treated tumors and an
FGFR2 rearrangement. This approval was based on the results of phase II, multicenter FIGHT-202 study.
In that trial, 146 patients with locally advanced or metastatic CCA were treated with pemigatinib at a dose
[55]
of 13.5 mg/day in a two-weeks on/one-week off schedule . Most of the patients (n = 107) had an FGFR2
fusion or rearrangement; after a median follow-up of 17.8 months, 36% of these patients had an objective
response to the therapy, and the responses were durable, with a median duration of response of 9.1 months,
median PFS of 6.9 months, and median OS an impressive 21.1 months. Grade ≥ 3 AEs occurred in 64% of
[55]
patients in the trial, with 45% having a serious AE (most frequently abdominal pain and pyrexia) . The
clinical benefit of pemigatinib in this setting will be further evaluated in a randomized trial with an active
comparator arm.

[56]
The pan-FGFR inhibitor infigratinib (BGJ398) was evaluated in a phase II study with CCA patients . In
that trial, including 61 previously treated patients with advanced CCA and an FGFR alteration, infigratinib
induced an ORR of 14.8% (18.8% in the cohort of patients with an FGFR2-fusion/alteration). An additional