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

demonstrated an ORR of 23% (95%CI: 11%-39%), a median PFS of 4.0 months (95%CI: 1.8-5.7 months), and
[69]
a median DOR of 10.8 months (95%CI: 0.7-25.4 months) . Adverse events of grade 3 or higher were
documented in 46% of patients, with alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
increases being the most common. Although the dual anti-HER2 therapy for HER2-positive BTC has not
received FDA approval, it is included as an option in the NCCN guidelines for patients who have
[21]
undergone prior treatment . To further confirm and establish the efficacy of the HER2-targeted treatment
in subsequent lines of therapy for BTC, future randomized controlled trials are essential.

Trastuzumab deruxtecan (T-DXd) has demonstrated encouraging anti-cancer efficacy in advanced solid
tumors that are HER2-positive, including BTC . A phase I study involving advanced HER2 mutant solid
[70]
tumors, excluding breast and gastric cancers, showed an ORR of 28.3%, and the median PFS reached 7.2
months (95%CI: 4.8-11.1 months). The HERB phase II study, which focused on BTCs, revealed an ORR of
36.4% (95%CI: 19.6%-56.1%) in patients with HER2-positive BTCs, along with a DCR of 81.8%
(95%CI: 59.7%-94.8%). The study also revealed a median OS of 7.1 months (95%CI: 4.7-14.6 months) and a
median PFS of 4.4 months (95%CI: 2.8-8.3 months) . However, the safety analysis revealed that 81.3% of
[31]
patients had grade 3 or higher TRAEs, with cytopenia being common. Of particular concern, approximately
25% of patients developed interstitial lung disease (ILD), along with significant gastrointestinal and
myelosuppression toxicities. This highlights the need for further investigation and follow-up.

Zanidatamab, a HER2-targeted bispecific antibody, underwent evaluation in the phase IIb HERIZON-BTC-
01 study (NCT04466891) in patients with HER2-amplified, locally advanced, unresectable, or metastatic
BTC. Among the 87 patients, 41.3% of participants had an objective response, with a DCR of 68.8%
(95%CI: 57.4%-78.7%). The median PFS reached 5.5 months (95%CI: 3.7-7.2 months), and data for median
OS were not yet mature at the time of data cutoff. However, the OS at 9 months reached 69.9% (95%CI:
57.8%-79.1%) .
[32]
Despite remarkable advances in HER2-targeted therapy, resistance continues to pose challenges in HER2-
positive BTCs. While resistance studies are primarily focused on breast and gastrointestinal cancers, they
provide valuable insights into potential resistance mechanisms in BTC. Notably, the intrapatient and
intertumor heterogeneity of HER2 expression is considered a critical factor contributing to primary
resistance [71,72] . Furthermore, HER2 positivity in BTC often coincides with other oncogenic drivers such as
[73]
FGFR, MET, and KRAS alterations, known to impart resistance to anti-HER2 therapy in in vitro studies .
Encouragingly, a small case series demonstrated the successful reversal of trastuzumab resistance by
[74]
combining HER2 blockade with inhibition of the secondary driver mutation . Additionally, in studies
involving gastric cancer patients, loss of HER2 has been linked to potential acquired resistance to anti-HER2
therapy [75,76] . Notably, the SUMMIT study evaluated an irreversible pan-HER tyrosine kinase inhibitor,
neratinib, in HER2-mutant advanced BTC, showing antitumor activity but not meeting the primary
endpoint; in one GBC patient, loss of HER2 amplification and reduction in VAF of the original HER2
mutation were demonstrated through biopsy and NGS . Combinatorial approaches, continuous
[77]
monitoring of HER2 alterations, and adaptive treatment regimens may offer potential solutions to improve
clinical outcomes and enhance the efficacy of HER2-targeted therapy in the management of BTCs.

Tropomyosin receptor kinase inhibitors
The neurotrophic tropomyosin kinase receptors (NTRK or TRK) family is a group of transmembrane
tyrosine kinases that hold significance in the development of neurons. These receptors are encoded by the
genes NTRK1, NTRK2, and NTRK3. In 1986, the first identification of somatic fusions involving the NTRK