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In 2020, NCCN guidelines recommended both larotrectinib and entrectinib as a front or subsequent-line
treatment for patients with BTCs carrying NTRK fusions.

Targeted immunotherapy
In 2017, the PD-1 inhibitor pembrolizumab was granted FDA approval as the first cancer therapy for any
solid tumor harboring a specific genetic feature, MSI-H or mismatch repair deficiency (dMMR), marking
[77]
the dawn of the era of tumor immunotherapy . The mechanism of mismatch repair is highly conserved,
and regulated by four genes: MLH1, MSH2, MSH6, and PMS2. Biallelic inactivation of any one of these
[78]
genes caused by mutations or epigenetic silencing results in dMMR and increased mutations . The
accumulated mutations, detectable through MSI testing, can further alter the status of tumor mutation
burden (TMB) by increasing the neoantigen rate, which is associated with the tumor microenvironment
and increased anti-cancer T cells in the periphery . The frequencies of MSI-H and TMB-H in iCCA were
[79]
approximately 1.2% and 3.7%, respectively . Accumulating evidence suggests that TMB-H (≥ 10 mut/Mb) is
[8]
more likely to benefit from PD-1 blockade immunotherapy, as is MSI-H [80-82] .

MSI-H/dMMR
The activity of immune monotherapy utilizing monoclonal antibody of PD-1 has been evaluated in solid
tumors of MSI-H/dMMR in substantial trials. KEYNOTE-158, a phase 2 basket trial, was designed to
investigate predictive biomarkers for immunotherapy using pembrolizumab in patients with advanced solid
tumors after previous treatment . In this trial, 321 patients with advanced non-colorectal cancer (22 with
[82]
cholangiocarcinoma) of MSI-H/dMMR were enrolled and evaluated for efficacy. The ORR was 30.8% (CR
8.4%; PR 22.4%), with mDOR of 47.5 months (95%CI 2.1+-51.1+). Furthermore, the percentages of patients
who achieved DOR ≥ 1 year, ≥ 2 years, and ≥ 3 years were 88.0%, 74.1%, and 70.1%, respectively. In
cholangiocarcinoma cohort, the ORR was 40.9% (CR 13.6%; PR 23.7%), and mDOR was 30.6 months
(95%CI, 6.2 to 40.5+), with mPFS of 4.2 months (95%CI 2.1-24.9) and mOS of 19.4 months (95%CI 6.5- not
reached). Thereby, the NCCN guideline of BTC also recommends the primary treatment of pembrolizumab
for patients with MSI-H/dMMR, but with limited trial data in the upfront setting. Additionally, the ongoing
phase 1 GARNET is currently assessing dostarlimab in patients with advanced solid tumors. In a
presentation of Cohort F, 106 evaluable patients with dMMR were enrolled, of which 99 had GI tumors
[83]
(including 2 with BTC) . The ORR was 38.7% (CR 7.5%; PR 31.2%), and mDOR was not reached. The
patient, either with biliary neoplasm or with gallbladder cancer, was confirmed to achieve CR. TRAEs were
reported in 68.8% of all patients, and 8.3% experienced grade ≥ 3 TRAEs.

TMB-H
Nivolumab combined with ipilimumab or nivolumab alone was assessed in CheckMate 848, a phase 2
randomized trial in patients with metastatic or advanced solid tumors of high tTMB or bTMB who were
immunotherapy-naïve and refractory to standard local therapies. In an oral presentation , the combination
[84]
arm exhibited improved ORR and survival in patients of tTMB-H. In tTMB-H cohort (n = 68) of dual
checkpoint inhibition, the ORR was 35.3%, with mPFS of 4.1 months (95%CI 2.8-11.3) and mOS of 14.5
months (95%CI 7.7- not evaluable).

The PD-L1 status was investigated for advanced BTC in a phase 2 trial of nivolumab, which enrolled 54
patients . The ORR in all patients was 22% by investigator assessment, but was merely 11% by independent
[85]
central review. The mPFS was 3.7 months (95%CI 2.3-5.7) with mOS of 14.2 months (95%CI 6.0 - not
reached). In the subgroup (n = 18) of PD-L1 positive (≥ 1% of tumor cells), the investigator-assessed and
centrally assessed ORRs were 50% and 28%, respectively, with mPFS of 10.4 months and mOS not reached.