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Gim et al. Hepatoma Res 2023;9:51 https://dx.doi.org/10.20517/2394-5079.2023.90 Page 11 of 20

[89]
with a favorable response observed in many cases to RET-directed therapy . Despite the overall rarity of
RET aberrations, their significance in driving oncogenesis highlights the need for further research and
understanding in order to explore potential therapeutic interventions.

Pralsetinib, a selective RET receptor tyrosine kinase inhibitor, has shown encouraging results in the phase 1/
2 ARROW trial, where it was evaluated in patients with solid tumors carrying RET fusions, including
[90]
BTC . The study showed an ORR of 57% (95%CI: 35%-77%), with a DOR of 11.7 months (95%CI: 5.5-19.0
months). The median PFS reached 7.4 months (95%CI: 5.1-13.6 months) and the median OS reached 13.6
months (95%CI: 7.5-NE) with a median follow-up of 23.5 months. Among the three BTC patients, two
participants had objective responses. In the safety analysis of 29 eligible patients, 20 patients (69%)
experienced grade ≥ 3 TRAEs, with the most frequent any-grade TRAEs being abnormal liver function tests.
Based on these findings, pralsetinib was approved by the FDA for advanced or metastatic RET-fusion-
positive lung and thyroid cancers [91,92] . While pralsetinib has not received FDA approval as a tumor-agnostic
drug, it is listed as a recommended option in the NCCN guidelines for both first-line and subsequent-line
treatment of RET-positive BTC .
[21]
Selpercatinib, a highly selective RET kinase inhibitor, was approved by the FDA for the treatment of any
RET-mutated solid tumors following promising data from the LIBRETTO-001 trial, a phase 1/2 basket trial
assessing its efficacy in solid tumors with RET fusion, regardless of their primary location [93,94] . Among 41
efficacy-evaluable patients, the ORR reached 43.9% (95%CI: 28.5-60.36), with a DOR of 24.5 months
(95%CI: 9.2-NE), including two BTC patients, one of whom had a response. The PFS was 13.2 months
(95%CI: 7.4-26.6) and the OS reached 18.0 months (95%CI: 10.7-NE). 38% of patients had grade ≥ 3 TRAEs,
with hypertension and abnormal liver function tests being frequently observed as grade 3 TRAEs.
Selpercatinib is currently recommended in the NCCN guidelines for both progressive and first-line
treatment of RET-positive BTC . Furthermore, its CNS activity highlights its potential in treating locally
[21]
advanced or metastatic solid tumors harboring RET fusions.

RET fusions exhibit diverse patterns, and the impact of fusion partners and breakpoints on drug response is
[95]
not fully understood . Despite an initial positive response, acquired resistance to RET inhibition treatment
[96]
inevitably emerges . While data on acquired resistance to RET inhibitors is growing, a comprehensive
understanding is not yet matured. Recent data in lung and thyroid cancer patients suggest that primary and
acquired resistance mechanisms converge on MAPK pathway activation . Therefore, employing a
[97]
sequential approach to RET-targeted therapy could require a combination of treatments involving
inhibitors that target distinct MAPK pathways. Furthermore, it appears necessary to reevaluate the
characterization of tumors treated with RET inhibitors when they show progression under RET inhibitor
therapy.

IMMUNOTHERAPIES FOR BILIARY TRACT CANCER
High tumor mutational burden
Programmed cell death ligand-1(PD-L1) is an immune checkpoint ligand that allows cancer cells to evade
[98]
immune recognition . Immunotherapy targeting PD-L1 or its receptor, programmed cell death 1 (PD-1),
has shown promising results in various cancers. Hypermutated tumors with a high tumor mutational
burden (TMB) are particularly responsive to immune checkpoint inhibitors [99,100] . TMB is the number of
somatic gene mutations present in a tumor and it serves as a biomarker for predicting the response to
immunotherapy . TMB-H, with a threshold of ≥ 10 mutations per megabase, indicates a high probability
[101]
of neoantigen formation and has been associated with improved outcomes in several cancer types.
Approximately 4% of all subtypes of BTCs are estimated to have TMB-H .
[19]