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Page 10 of 21 Yang et al. Hepatoma Res 2023;9:48 https://dx.doi.org/10.20517/2394-5079.2023.68

EGFR pathway and HER2 aberrations
The epidermal growth factor receptor (EGFR) is a member of the ERBB family (including ERBB1/EGFR/
HER1, ERBB2/HER2/Neu, ERBB3/HER3, and ERBB4/HER4) of receptor tyrosine kinases. The activation of
downstream signaling pathways, including RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, PLCγ/PKC, and
STAT, is initiated by the binding of epidermal growth factor (EGF), transforming growth factor α (TGF-α),
or nerve growth factor (NGF), and results in persistent pathway activation that promotes tumor cell
proliferation, invasion and metastasis [49,50] . Targeted therapy against the ERBB family is currently considered
a pivotal approach in tumor treatment, commonly using two categorical drugs: monoclonal antibodies and
small molecule tyrosine kinase inhibitors (TKI) . Monoclonal antibodies primarily impede signal
[51]
transduction by obstructing ligand binding or interfering with receptor dimerization. For instance,
cetuximab and panitumumab specifically target EGFR, while trastuzumab and pertuzumab effectively target
HER2. On the other hand, small molecule TKIs competitively bind to the receptor kinase domain to inhibit
signal transduction. Notable examples include selectively targeting EGFR with gefitinib, erlotinib, or
osimertinib, and targeting HER2 with lapatinib, neratinib, or tucatinib. Although EGFR/ERBB1 mutations
and amplifications have been reported in CCA, none of the Phase 2/3 trials targeting EGFR in CCA have
shown substantial improvement in survival over the past few decades. HER2 gene (also known as Neu/
ERBB2) encodes product HER2 protein, which enhances invasion, motility, and proliferation of
cholangiocarcinoma cells and exerts carcinogenic effects by activating the ERBB receptor family . ERBB2
[52]
gene amplification is observed in approximately 5%-15% of BTC and about 1.6%-4% of iCCA [8,9,11] . ERBB2
mutation accounts for around 1.6% of iCCA . Interestingly, targeted treatment against HER2 amplification,
[8]
together with overexpression in BTC, has made more progress.

Trastuzumab plus pertuzumab
Trastuzumab, the monoclonal antibody targeting the subdomain IV of the extracellular domain of HER2
receptor, inhibits downstream PI3K/AKT and Ras/MEK signaling pathways to exert anti-tumor effects .
[53]
Pertuzumab is a HER-2 inhibitor targeting the subdomain II of the extracellular domain. MyPathway study,
a phase 2a multi-basket trial of trastuzumab combined with pertuzumab, enrolled 39 advanced BTC
patients (18% with iCCA) who had HER2-amplified, overexpressed or both . In BTC cohort, the ORR was
[54]
23% and mDOR was 10.8 months, with mPFS of 4.0 months (95%CI 1.8-5.7) and mOS of 10.9 months
(95%CI 5.2-15.6). This regimen is thus recommended as subsequent therapy for HER2-positive BTC in
NCCN guidelines (2022). However, in iCCA subset (n = 7), the ORR was 0% and mDOR was not applicable,
with mPFS of 2.6 months (95%CI 1.0-5.3) and mOS of 3.9 months (95%CI 1.2-8.1). Grade 3-4 AEs were
reported in 46% of BTC patients, and the most frequent AEs were elevated alanine aminotransferase and
aspartate aminotransferase (each 13%).

Other ERBB2 alterations inhibitors
Trastuzumab deruxtecan (DS-8201/T-DXd), a new drug of antibody-drug conjugates consisting of a HER2-
monoclonal antibody, a chemical linker, and a topoisomerase I inhibitor, was investigated in a phase 2
[55]
single-arm study (HERB trail) among patients with HER2-expressing BTC . Among 22 HER2-positive
BTC patients (3 with iCCA) identified for analysis, the ORR was 36.4% (2 CR and 6 PR), with mPFS of 4.4
months (95%CI 2.8-8.3) and mOS of 7.1 months (95%CI 4.7-14.6).

Neratinib, an irreversible inhibitor targeting pan-HER tyrosine kinase, exhibits efficacy against HER2-
mutant tumors. SUMMIT trial, its phase 2, single-arm, basket study in solid tumors carrying HER2
mutations, enrolled 25 BTC patients (11 cholangiocarcinoma including 6 iCCA, 10 gallbladder and 4
ampullary cancer) . In BTC cohort, the ORR was 16%, and DORs for the 4 PR patients were 3.0, 3.6
[56]
(censored), 3.7, and 4.7 months, respectively, with mPFS of 2.8 months (95%CI 1.1-3.7) and mOS of 5.4
months (95%CI 3.7-11.7).