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Page 12 of 21 Yang et al. Hepatoma Res 2023;9:48 https://dx.doi.org/10.20517/2394-5079.2023.68

mPFS was 11.4 months (95%CI 8.4-16.3), while mOS achieved 28.6 months. Three of 4 patients with iCCA
exhibited a PR, with individual PFS of 12.8, 9.1, and 29.4 months, respectively. The most frequent AEs were
fatigue (74%), nausea (57%), fever (51%) and chills (54%). In 2021, this regimen was recommended as a
subsequent-line therapy for BTCs with BRAF V600E mutation in NCCN guidelines.

Other RAS/RAF/MEK/ERK pathway inhibitors
VE-BASKET, a phase 2, single-arm, basket trial of vemurafenib in non-melanoma cancers with BRAF V600
mutations, enrolled 9 patients with cholangiocarcinoma (8 with BRAF V600E; 1 with V600X) . Two of the
[67]
9 patients achieved PR with a DOR of 3.6 and 22.1 months, respectively. The mPFS was 3.0 months, while
the mOS was 11.2 months.

Binimetinib, a selective MEK1/2 inhibitor, was assessed in combination with capecitabine in a phase 1b trial.
A total of 34 patients (26 detected for mutations using NGS) with advanced BTC were enrolled after prior
gemcitabine-base treatment . The ORR, mPFS, and mOS were 20.6%, 4.1 months (95%CI 2.8-5.7), and 7.8
[68]
months (95%CI 5.9-12.2), respectively. The patients with mutant-type (n = 10) on RAS/RAF/MEK/ERK
pathway (7 on KRAS; 2 on MAP2K1; 1 on NRAS) exhibited superior outcomes than those with wild-type (n
= 16), in terms of ORR (40.0% vs. 12.5%, P = 0.028), mPFS (5.4 vs. 3.5 months, P = 0.010), and mOS (10.8 vs.
5.9 months, P = 0.160).

RET fusions
The RET gene is an oncogene that encodes the tyrosine kinase receptor superfamily RET protein. The
tumorigenic activation of RET can take place through two mechanisms: one involves chromosomal
rearrangements, by which RET kinase domain is fused with a partner protein containing a dimerization
domain; the other involves RET mutations, which results in direct or indirect kinase activation. The fusion
of the RET gene can cause ligand-independent dimerization and constitutive activation of RET kinase,
thereby inducing cell overproliferation and tumor formation by activating downstream pathways such as
RAS-MARK, PI3K-AKT, JAK-STAT, PLCγ, etc. RET fusion genes are widely distributed across various
types of cancer. Despite the low incidence in iCCA population, many individuals carrying RET fusions may
still benefit from targeted therapies. Although previous multi-kinase inhibitors like cabozantinib and
vandetanib have shown moderate activity against RET-driven malignancies, recent selective inhibitors such
as selpercatinib and pralsetinib have demonstrated significant efficacy against both mutations and fusions.

Pralsetinib
Pralsetinib, a selective inhibitor targeting RET receptor tyrosine kinase, was investigated in phase 1/2 trial
[69]
ARROW in patients with advanced solid tumors harboring RET fusion . Twenty-nine patients with 12
types of tumors, excluding NSCLC and thyroid cancer, who had previously received or were not eligible for
standard therapies, were enrolled. In 23 evaluable patients (3 with cholangiocarcinoma), the ORR achieved
57% and mDOR was 11.7 months (95%CI 5.5-19.0). Notably, PR was achieved in two cholangiocarcinoma
patients, including one iCCA patient, who was enrolled with the best response of PD on three lines of
previous therapy and received pralsetinib for more than 20 months. The mPFS was 7.4 months (95%CI 5.1-
13.6), with mOS of 13.6 months (95%CI 7.5- not reached). The most frequent grade ≥ 3 TRAEs were
neutropenia (31%), anemia (14%), and increased aspartate aminotransferase (AST) (10%).

Selpercatinib
Selpercatinib, a highly selective inhibitor of the RET kinase with CNS activity, was assessed in phase 1/2 trial
IBRETTO-001 for patients with advanced solid tumors harboring RET fusion . A total of 45 patients with
[70]
14 kinds of tumors, excluding lung and thyroid cancer, who had experienced progression on prior systemic