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Currently, results from randomised controlled phase III trials recruiting patients with FGFR2-
fusions/rearrangements that compare the standard of care (CisGem) with different FGFR inhibitors in first-
line setting are awaited (pemigatinib, NCT03656536; infigratinib, NCT03773302; futibatinib,
[9]
NCT04093362) .

The whole plethora of FGFR-targeted therapies, characterised by different mechanisms of action, offers a
unique opportunity for a paradigm shift in the treatment of a subgroup of patients with advanced BTCs,
providing the potential for personalised treatment with active compounds and a sequential approach to be
investigated in the next future. The challenge of primary and secondary resistance limits the efficacy of this
class of drugs [83-85] . Exploring the potential of combining FGFR inhibitors with other treatments able to
target signalling shared by wild-type and resistant tumour cells may help prevent the emergence of
resistance mutations. This strategy stands on the biological rationale that blocking a driver kinase is more
efficacious when downstream pathway components are targeted as well [86,87] .

Expanding precision medicine in aBTCs: challenges and opportunities
Despite the opportunity to improve treatment and outcomes in a personalised manner, a major challenge,
consisting in the design (and conduction) of adequately powered clinical trials in small patient subgroups,
limits a rapid and effective drug development process based on traditional clinical trials design. However,
the advent of precision medicine has been followed by novel clinical trial models to identify biomarker-
matched subgroups of patients likely to benefit from specific targeted therapies, independently from
histology. The overall objective of this innovation is to answer multiple questions at the same time and more
efficiently in order to accelerate clinical drug testing and approval. In this light, novel strategies such as
platform studies with adaptive designs which consider innovative endpoints may represent a potential
opportunity to advance the precision drug development process in rare tumours such as BTCs. Recently,
basket trials have been developed to investigate the efficacy of molecular-targeted therapy for similar
[88]
oncogene-defined subgroups across different tumour types .

The activity of the BRAF V600 kinase inhibitor vemurafenib has been explored in a basket trial enrolling
120 patients with refractory BRAF mutated cancers. In the BTCs patient cohort, vemurafenib monotherapy
showed 62% of DCR .
[89]

Another phase II basket trial of the BRAF inhibitor dabrafenib in combination with the MEK inhibitor
trametinib in multiple refractory tumour types with BRAFV600E mutation showed ORR in 51% (22/43) of
patients with BTCs . Common treatment-related adverse events included pyrexia, rash, and nausea. The
[90]
most common grade 3 or worse adverse event was increased γ-glutamyltransferase in five (12%) patients.
No treatment-related deaths were reported. Further investigation in larger trials is warranted to confirm
these early promising results.

A similar experience included 251 patients with 35 different advanced refractory tumour types with
alterations in HER-2, EGFR, BRAF, and Hedgehog pathway, who were treated with pertuzumab plus
trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively . In the small BTCs cohort (n = 7),
[91]
HER-2 targeted therapy (trastuzumab plus pertuzumab) resulted in objective response in two patients while
[91]
three patients experienced durable response (disease stability > 6 months) .

In another basket trial of patients with HER-2 or HER-3 mutations treated with neratinib, 2/9 patients of the
BTCs cohort experienced partial response .
[90]