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Page 10 of 20 Gim et al. Hepatoma Res 2023;9:51 https://dx.doi.org/10.20517/2394-5079.2023.90

genes was reported in a colorectal cancer patient. Subsequently, it was uncovered that mutations in NTRK
genes, most commonly NTRK fusions, are associated with oncogenesis in various tumor types. The NTRK
[78]
mutations are more common in patients with lung cancers and soft tissue tumors . The estimated
[15]
prevalence of NTRK fusions in BTC is 0.75% .

To date, the FDA has approved two first-generation NTRK inhibitors as first-line and subsequent line of
[80]
therapy in patients with NTRK fusion-positive BTC: larotrectinib and entrectinib . In November 2018,
[79]
the FDA granted accelerated approval to Larotrectinib based on results from three multicenter clinical trials:
LOXO-TRK-14001, SCOUT, and NAVIGATE. A pooled analysis of the three studies showed an ORR of
69% (95%CI: 63-75), with more than one-fourth of the cases (26%) achieving a complete response (CR) .
[81]
The response has shown considerable durability, with a median DOR of 32.9 months (95%CI: 27.3-41.7).
The median PFS reached 29.4 months (95%CI: 19.3-34.3). The median was not reached at a median follow-
up of 32.2 months. The TRAEs were primarily in grade 1 or 2, and 20% of patients had grade 3 or 4 adverse
events, leading to treatment discontinuation in five cases.

Entrectinib was approved by the FDA in the subsequent year for adults and pediatric patients who have
solid tumors with NTRK gene fusion based on favoring data from three multicenter, single-arm clinical
trials: ALKA, STARTRK-1 (NCT02097810) and STARTRK-2 (NCT02568267) . An updated pooled
[82]
analysis data of the three phase 1-2 trials from the 2022 ASCO annual meeting has demonstrated
meaningful clinical response and good tolerability . The ORR was 61.3% (95%CI: 53.1%-69.2%), with more
[83]
than one-fourth of those who had responses achieving a CR. The median DOR reached 20.0 months
(95%CI: 13.2-31.1 months) and the PFS reached 13.8 months (95%CI: 10.1-20.0 months). At a median
survival follow-up of 30.6 months, the median OS reached 37.1 months (95%CI: 27.2-NE). Moreover, the
TRAEs were mainly grade 1-2: dysgeusia (36.6%), diarrhea (29.8%), and weight gain (28.5%). A total of 7.2%
of patients needed to discontinue the treatment due to adverse events.

While a significant portion of patients with NTRK fusion-positive cancers achieve enduring disease control,
the emergence of resistance to TRK inhibition remains a substantial challenge . This emphasizes the
[84]
critical need to develop second-generation TRK inhibitors and/or explore strategies to counter this
resistance mechanism. A recent study examining post-progression tumor tissue through NGS from patients
treated with first-generation TRK inhibitors found that the majority displayed on-target resistance (83%) as
[85]
opposed to off-target resistance (11%) or an unidentifiable mechanism (6%) . Among patients exhibiting
on-target resistance, mutations primarily affected the solvent front (87%) and, to a lesser extent, the
gatekeeper region (13%). The sequential use of next-generation therapy appears to impact the pattern of
mutation occurrence and development. At present, several next-generation TRK inhibitors, such as
selitrectinib, repotrectinib, and taletrectinib, are undergoing evaluation in clinical trials due to their
promising preclinical activity . These innovative agents hold considerable potential in addressing the
[86]
resistance challenge that may arise with the use of first-generation TRK inhibitors.

RET inhibitors
For over three decades following the identification of the RET gene that encodes the receptor tyrosine
[87]
kinase, mutations in the RET gene have been identified as actionable drivers of oncogenesis . Specific RET
fusion proteins can initiate tumorigenesis and progression of cancer by stimulating subsequent signaling
cascades, ultimately resulting in unregulated cell growth. While RET gene fusions are relatively rare in BTC,
they are identified in around 1% to 2% of other types of cancer, such as NSCLC and thyroid cancers,
indicating the promise of targeting RET kinase in therapeutic interventions . Activating aberrations in
[88]
RET, including mutations, fusions/rearrangements, or amplifications, are found in about 1.8% of all tumors,