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Gim et al. Hepatoma Res 2023;9:51 https://dx.doi.org/10.20517/2394-5079.2023.90 Page 7 of 20

Both studies evaluating pemigatinib and futibatinib showed a similar side effect profile.
Hyperphosphatemia, alopecia, and diarrhea were the most frequent TRAEs noted with both drugs. In the
case of pemigatinib, these side effects were mostly in grade 1 or 2. Among grade 3 or more severe adverse
[42]
events, hypophosphatemia was the most frequently reported, occurring in 14.3% of cases . Similarly, for
futibatinib, the most common grade 3 TRAE was hyperphosphatemia, seen in 30% of participants .
[45]
Additionally, other notable grade 3 adverse events included increased aspartate aminotransferase levels
(7%), stomatitis (6%), and fatigue (6%).

Several ongoing trials hold the potential to provide promising data in the near future. One of these is the
phase II FIDES-01 study, investigating derazantinib, a pan-selective FGFR inhibitor, in patients with
M/A
F
pretreated iCCA harboring FGFR2 fusion (FGFR2 ) or FGFR mutation/amplification (FGFR2 ). Data
from the 2022 ESMO Congress showed a higher ORR of 21.4% (95%CI: 13.9%-30.5%) in FGFR2 compared
F
to 6.5% in FGFR2 cohort (95%CI: 0.8%-21.4%) . The median OS was documented as 17.2 months
[29]
M/A
F
(95%CI: 12.5%-22.4%) and the median PFS reached 8.0 months (95% CI: 5.5%-8.3%) in FGFR2 patients.
In the ongoing ReFocus trial (NCT04526106), RLY-4008, a highly selective FGFR2 inhibitor, is being
evaluated in advanced solid tumors, including FGFR inhibitor-naïve BTC. Preliminary data from the 2022
ESMO Congress showed a promising ORR of 88.2% (95%CI: 63.6%-98.5%) in 17 patients who received the
[30]
recommended phase 2 doses . Notably, one patient achieved a near-complete response and underwent
curative tumor resection. The encouraging findings underscore the significance of further monitoring the
ongoing development of RLY-4008 as a potential treatment option for advanced stages and potentially in
the neoadjuvant setting.

The encouraging data on FGFR inhibitors in BTC holds promise, but there are significant challenges to
overcome, particularly concerning acquired resistance to these inhibitors. Numerous preclinical
investigations have been conducted to identify the underlying mechanisms of resistance, including bypass
signaling, epithelial-mesenchymal transition (EMT), and the development of secondary FGFR mutations,
commonly referred to as gatekeeper mutations . However, it is vital to acknowledge that the majority of
[47]
research in this area has primarily centered on urothelial, lung, and gastric cancer cell lines, potentially not
encompassing the complete range of resistance mechanisms observed in BTC. Moreover, in vitro cell
models may not entirely capture the heterogeneity and complexity of human disease, adding another layer
of consideration in interpreting the findings and applying them to BTC treatment strategies.

BRAF inhibitors
The mitogen-activated protein kinase (MAPK) signaling pathway, which includes the RAS/RAF/MEK/ERK
pathway, plays an essential role in cellular proliferation and survival . BRAF, an oncogene, activates the
[48]
RAS/RAF/MEK pathway. BRAF mutations, particularly the V600E mutation, are commonly observed in
various solid tumors, including colorectal malignancy, non-small cell lung cancer (NSCLC), and
[51]
melanoma [49,50] . The BRAF V600E mutation activates BRAF, resulting in tumor growth and metastasis .
BRAF activating mutations are rare in BTC, comprising approximately 5.5% of cases, with 1.5% of BRAF
V600E mutation in iCCA and 0.5% of BRAF V600E in GBC .
[12]
Combining the RAF inhibitor, dabrafenib, with the MEK inhibitor, trametinib, has shown encouraging
results in the treatment of BRAF-mutated BTC. The phase II ROAR trial investigated the effectiveness of
combining dabrafenib and trametinib in patients with advanced solid tumors harboring the BRAFV600E
mutation who had experienced the progression of disease after prior treatment . The trial showed a
[52]
significant ORR of 51%, with a mean OS of 14 months and a mean PFS of 9 months. The dabrafenib and