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Yang et al. Hepatoma Res 2023;9:48 https://dx.doi.org/10.20517/2394-5079.2023.68 Page 11 of 21

Zanidatamab (ZW25), a novel bispecific antibody, targets extracellular subdomains IV and II, which are
targeted by trastuzumab and pertuzumab, respectively. HERIZON-BTC-01, its phase 2 single-arm trial in
BTC patients with HER2-amplification after prior gemcitabine-base treatment, enrolled 80 patients with
[57]
HER2 immunohistochemistry (IHC) 2+ or 3+ . In these patients (23 with iCCA), the ORR was 41.3%
(30.4% in iCCA) and mDOR was 12.9 months (95%CI 6.0- not estimable), with mPFS of 5.5 months (95%CI
3.7-7.2) and immature mOS. The grade 3 TRAE rate was 18%, with the most frequent TRAEs of diarrhea
(5%) and decreased ejection fraction (3%). No grade 4/5 TRAEs were observed.

BRAF and KRAS mutations
The BRAF and KRAS genes play crucial roles in signaling pathways that regulate cell growth and
differentiation. BRAF, also known as proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene
homolog B, encodes serine/threonine-protein kinase B-Raf . B-Raf belongs to the Raf kinase family of
[58]
proteins involved in growth signal transduction, and functions to regulate the MAP kinase/ERKs pathway,
which impacts cell division, differentiation, and secretion. B-Raf mutation was discovered in certain human
[59]
tumors . About 5% of iCCAs harbor BRAF mutations, with the most prevalent type of BRAF V600E. iCCA
patients carrying BRAF V600E exhibit higher cancer stage, greater lymph node involvement, and poorer
overall survival, compared to those without such mutation . Recently, combined inhibition along the RAS-
[60]
RAF-MEK-ERK pathway targeting BRAF V600E has demonstrated significant clinical activities.

KRAS proto-oncogene, a member of the RAS superfamily that also includes H-RAS and N-RAS, is
frequently mutated in human cancers. The KRAS-encoded protein is a small GTPase that plays a crucial
role in regulating multiple signaling pathways, including MAPK, PI3K, and Ral-GEFs, thereby impacting
[61]
cellular growth, differentiation, survival, and migration . KRAS mutations occur in 6% to 20% of iCCA
patients [8,9,12,13] , predominantly at codon 12 or 13 on exon 2. The most prevalent mutations are G12D and
G12E , which result in the impaired ability of KRAS protein to hydrolyze GTP to GDP after binding to
[62]
GTP, thereby leading to a persistent activation. Consequently, this sustained activation excessively
stimulates downstream signaling pathways and facilitates the initiation and progression of iCCA. Currently,
there are two main treatment strategies for KRAS mutations: one involves direct inhibition of KRAS protein
or its GTP binding capacity, exemplified by sotorasib (AMG 510) and adagrasib (MRTX849) targeting
G12C in non-small cell lung cancer (NSCLC); the other entails indirect inhibition of downstream signaling
pathways or upstream regulatory factors associated with KRAS, such as MEK inhibitors and SOS1
[62]
inhibitors . For iCCA, further research is currently needed [63,64] .

Darafenib plus trametinib
Dual inhibition of BRAF and MEK (dabrafenib plus trametinib) was evaluated and approved as the first
tissue-agnostic treatment for patients with solid tumors harboring BRAF V600E mutation, on the basis of
phase 2 Rare Oncology Agnostic Research (ROAR) and NCI-MATCH studies. Concerning iCCA,
[65]
[66]
ROAR study, a single-arm and basket trial, enrolled 43 BTC patients (iCCA accounted for 91%) after
previous systemic treatment . In BTC cohort, the independent review ORR reached 47%, and mDOR was
[65]
9 months. Among responded BTC patients, 59% of them had a DOR > 6 months, and 7 patients had a DOR
> 12 months. The mPFS was 9 months (95%CI 5-10), and mOS achieved 14 months (95%CI 10-33). This
cohort experienced serious AEs (40%) and TRAEs (21%), with pyrexia being the most frequent AE (19%).
No deaths of TRAE were reported.

In EAY131-H study (the subprotocol H of NCI-MATCH trial), this dual inhibition was evaluated in
patients with BRAF V600-mutant refractory solid tumors (including 4 iCCA patients), lymphoma or
multiple myeloma . In 29 patients for analysis, the ORR was 37.9%, with a mDOR of 25.1 months. The
[66]