Page 816 - Read Online

Page 10 of 15 Alqahtani et al. Hepatoma Res 2020;6:70 I http://dx.doi.org/10.20517/2394-5079.2020.65

target [78,79] . In a phase I trial, the STAT3 inhibitor ABC294640 showed activity in CCA, and the inhibitor is
under further evaluation in a phase II trial (NCT03377179).

[80]
Amplification and overexpression of MET have been described in CCA, with associated poor prognosis .
Clinical studies evaluating MET inhibitors in monotherapy revealed limited clinical activity. In contrast,
phase I data of a study evaluating the combination of the MET inhibitor tivantinib with gemcitabine in
[81]
patients with metastatic solid cancers suggest the presence of antitumor activity . However, phase II data
failed to show an ORR, PFS, or OS benefit from the addition of the MET inhibitor merestinib to first-line
[76]
Gem-Cis in patients with advanced biliary tract cancer .

IMMUNE CHECKPOINT INHIBITION FOR CCA
Over the last decade, immune checkpoint inhibitors have revolutionized the treatment landscape of many
different cancer types, and this strategy is being explored in CCA.

Pembrolizumab is a monoclonal antibody directed against the programmed death-1 receptor (PD-1).
In 2017, the FDA had approved pembrolizumab for the treatment of microsatellite instability-high solid
tumors. In the phase II Keynote-158 trial, the antibody had robust clinical activity in patients with non-
colorectal microsatellite instability-high/mismatch repair-deficient solid tumors. Two hundred and
thirty-three patients, including 22 with advanced CCA, were enrolled in the study. Pembrolizumab was
[82]
administered at a dose of 200 mg once every three weeks for a maximum of two years . An overall
response rate of 34.3% was reported, with a median duration of response that was not yet reached after a
median follow-up of 13.4 months. Among the cohort of CCA patients, the ORR was 49%, and two patients
had a complete response; the median OS in CCA patients was 24.3 months. Treatment-related AEs -
most commonly fatigue (14.6%), pruritus (12.9%), and diarrhea (12.0%) - occurred in 64.8% of patients;
Grade ≥ 3 treatment-related AEs occurred in 14.6% of patients, and 23.2% experienced an immune-related
[82]
AE . Thus, these data establish pembrolizumab as an effective and safe treatment option for patients with
[83]
CCA and mismatch repair deficiency. According to Silva et al. , 5%-10% of patients with CCA meet this
criterion.

Pembrolizumab was also evaluated in non-mismatch repair-deficient CCA patients. In the large multi-
cohort, phase Ib Keynote-028 trial, 24 patients with PD-L1-positive CCA were treated with pembrolizumab
[84]
at a dose of 10 mg/kg every two weeks for up to two years . In this cohort, four patients (17%), three
with CCA and one with gallbladder cancer, had a partial response, and four patients (17%) had disease
stabilization; at 12 months, 27.6% of patients were still alive. The rate of Grade 3 toxicities was 16.7%, with
[84]
no reported Grade ≥ 4 toxicities .

The PD-1 inhibitor nivolumab has also been evaluated in patients with biliary tract cancer. In a study of 30
patients with metastatic disease, nivolumab was associated with an ORR of 20% and a disease control rate
[85]
of 60%; the median PFS was 3.1 months . Preliminary results of an ongoing phase II trial in patients with
advanced refractory biliary tract cancer indicate an ORR of 22%, with a disease control rate of 60%. The
median OS in this study was 14.2 months, with 6- and 12-month OS rates of 71.4% and 52.3%, respectively.
At six months, 35.2% of patients were free of progression; the rate was 24.1% at 12 months. The safety
profile was in line with that of previous reports on nivolumab. Importantly, this trial did not select for PD-
[86]
L1 expression at study entry . In a Japanese trial, nivolumab was evaluated as monotherapy or combined
with chemotherapy in 60 patients with biliary tract cancer; the monotherapy was associated with a median
OS of 5.2 months, a median PFS of 1.4 months, and a low ORR, with only one patient obtaining a response.
In the combined therapy cohort, median OS (5.4 months) and median PFS (4.2 months) were longer, and
[87]
11 of 30 patients had an objective response .