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Page 14 of 23 Casolino et al. Hepatoma Res 2021;7:76 https://dx.doi.org/10.20517/2394-5079.2021.79

The overall disappointing results achieved with ICIs monotherapy in BTCs compared to other tumour types
can be explained by their biological features. BTCs are characterised by “cold” TME that lacks dendritic cells
and effector T cells, essential for an effective immunomodulatory activity [97,98] . A different TME/immune cell
infiltrate may also explain the higher sensitivity to ICIs observed in patients with hepatocellular
carcinoma .
[99]
The only subgroup of patients with higher sensitivity to ICIs is that with dMMR/MSI high, as already
mentioned. This genomic alteration represents the only potential biomarker that can predict the activity of
this class of drugs identified to date. In the BTC cohort of 22 patients enrolled in the KEYNOTE-158 phase
II study evaluating pembrolizumab in previously-treated patients with advanced non-colorectal
dMMR/MSI high cancer, the ORR was 40.9% (including complete response in 2 patients), mPFS 4.2
[100]
months, and mOS 24.3 months . The biological explanation of these results is that cancers with
dMMR/MSI high (either due to inherited germline variants or epigenetic inactivation of MMR genes) are
associated with a high degree of somatic mutations and have peculiar biological characteristics such as
increased expression of neoantigens, abundant tumour-infiltrating lymphocyte (TIL), and high tumour
mutational burden (TMB) that stimulate the immune checkpoint axis. Beyond dMMR/MSI-H, TMB is
emerging as an additional predictive biomarker for PD-1/PD-L1 immune checkpoint inhibitors. A whole-
exome-sequencing study of paired tumour/normal BTCs showed that 6% (14/239) were defined as high
TMB using a threshold of > 11.13 Δ/Mb, which corresponded to a median of 641 non-silent mutations in
this subset of hypermutated tumours. Hypermutation was associated with concurrent MMR deficiency
[57]
and/or MSI in about 36% of cases .
Given to poor results achieved with immune checkpoint inhibitors monotherapy, combinatorial strategies
to enhance the efficacy of this class of drugs in patients with BTCs are currently under clinical investigation.
One promising approach is represented by immunotherapy-chemotherapy combination. The anti-PD-1
nivolumab has been associated with CisGem chemotherapy in phase II clinical trials. The association
resulted in 37% ORR and mPFS and mOS of 4.2 and 15.4 months . Phase III studies aimed at assessing the
[101]
clinical efficacy of this therapeutic opportunity are currently ongoing, including the TOPAZ-1 and
KEYNOTE-966, in which patients are randomised towards receiving CisGem alone or in combination with
the anti-PD-L1 durvalumab or and PD-1 pembrolizumab, respectively. A phase II trial is investigating the
activity of the triplet combination of durvalumab, tremelimumab (anti-CTLA-4), and paclitaxel
(NCT03704480).

The inhibition of the transforming growth factor β (TGF-β) pathway has shown promising preliminary
results. Bintrafusp alfa (M7824) is a first-in-class bifunctional fusion protein composed of the extracellular
domain of the transforming growth factor (TGF)βRII receptor (a TGF-β trap) fused to a human IgG1
monoclonal antibody blocking PD-L1. It has been tested in an expansion cohort from a phase 1 study
(NCT02699515), including 30 patients with advanced refractory BTCs. The ORR by central assessment was
20%, mPFS was 2.6 months and mOS 12.7 months . However, despite initial enthusiasm, results from
[99]
recent phase II clinical trials showed disappointing results in first- and second-line settings. Single-agent
bintrafusp alfa demonstrated efficacy, durability, and an acceptable toxicity profile when used in patients
with locally advanced or metastatic BTC who failed or were intolerant to frontline chemotherapy platinum-
based chemotherapy, according to recent data from the phase 2 INTR@PID BTC 047 trial (NCT03833661).
After more than 9 months of follow-up, the independent review committee adjudicated an ORR of 10.1%
(95%CI: 5.9%-15.8%). Despite the benefit showcased, the trial did not meet the predefined threshold that
[102]
would have allowed for regulatory filing for the agent’s use in the second-line treatment of BTC .
Bintrafusp alfa was also under investigation in combination with CisGem in the frontline treatment of