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Basket trials have also demonstrated the clinical activity of tropomyosin receptor kinase (TRK) inhibitors in
TRK fusion-positive cancers. Entrectinib and Larotrectinib are potent, highly selective inhibitors of
tropomyosin TRK A, B, and C, which has been shown promising results with RR up to 75% in NTRK gene
[90]
fusion-positive advanced solid tumours, including BTCs, in early-phase trials . The long duration of
response (10 months for entrectinib and not reached for larotrectinib), and the good tolerability, led to
expedite approval from the FDA in 2018 and 2019 for larotrectinib and entrectinib for patients with
histology-agnostic solid tumours harbouring NTRK fusions. Although present in a small percentage of
BTCs patients (3%-5%), NTRK fusion constitutes a promising therapeutic target to further investigate in this
disease. NTRK inhibitors are currently being explored in clinical studies, which include advanced BTCs
(NCT02576431, NCT02568267).

The above-mentioned studies demonstrate that histology-independent, biomarker-driven trials are feasible
and represent a potential tool for developing targeted therapies for small - molecularly selected - patient
subgroups of refractory cancers, thus constituting a unique opportunity to advance the paradigm shift from
unselected to genome-driven oncology. However, major efforts are necessary to expand biomarker-directed
clinical trials that are adequately powered for small groups of patients with a wide range of potentially
actionable genetic aberrations.

In this context, several studies based on tumour sequencings such as TAPUR (NCT02693535) and MATCH
(NCT02465060) trials are investigating the clinical activity of a series of compounds in patients with
advanced solid tumours, including BTCs. The rationale is that patients with genetic abnormalities (such as
mutations, amplifications, or translocations) may benefit from treatments matching the genetic profile that
are either in clinical trials or already approved for the treatment of other cancer types.

Immunotherapy
Immunotherapy based on monoclonal antibodies targeting the immune checkpoint regulators such as
cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) or programmed
death ligand 1 (PD-L1), has emerged as a promising therapeutic strategy for several tumour types, including
melanoma, non-small cell lung cancer, urothelial carcinoma, renal-cell carcinoma, head and neck cancer,
and hepatocellular carcinoma . In contrast, this strategy was associated with modest efficacy in unselected
[92]
patients with aBTCs [93,94] . The only FDA-approved immunotherapy in BTCs is pembrolizumab, an
anti-PD-1 antibody, which received tissue-agnostic approval for the treatment of advanced solid tumours
with DNA mismatch repair deficiency (dMMR) or microsatellite instability (MSI), including those of the
[95]
biliary tract (< 3% cases) .
The safety and activity of Pembrolizumab in patients with aBTCs have been investigated in the phase 1b
multicohort study KEYNOTE-028 (NCT02054806) and the phase 2 multicohort study KEYNOTE-158
(NCT02628067), respectively . PD-L1 positive tumours were required for eligibility in KEYNOTE-028
[96]
only. These two studies demonstrated that pembrolizumab monotherapy provides durable antitumor
activity in 6% to 13% of patients with advanced BTC, regardless of PD-L1 expression, and has a manageable
toxicity profile. In KEYNOTE-028, ORR was 13% (3/23), mOS and mPFS were 5.7 and 1.8 months. In
KEYNOTE-158, ORR was 5.8% (6/104), mOS and mPFS were 7.4 and 2 months. ORR was 6.6% (4/61) and
2.9% (1/34) among PD-L1-expressers (n = 61) defined by using a threshold of ≥ 1% of tumours cells or
[96]
infiltrating lymphocytes expressing PD-L1, and PD-L1-nonexpressers (n = 34), respectively . Whether this
improved ORR translates into improved longer overall survival in patients with PD-L1-negative tumours
remains unclear.