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The phrase II, single-arm study, ROAR, examined 43 previously treated individuals with advanced BTC
[50]
carrying documented mutations . These individuals underwent combination inhibition of the MEK
pathway and the BRAF pathway. The ORR was 47%, with a median PFS of 9 months and a median OS of 14
months. However, around 40% of patients experienced serious adverse events, including elevated γ-glutamyl
transferase, fever, reduced white blood cell count, and increased blood pressure.

To evaluate the potential survival advantage of this treatment compared to chemotherapy as an earlier line
of systemic therapy, larger studies would be required.

Other mutation-based therapy
One analyzed study included 54 adults with advanced or metastatic solid tumors positive for NTRK fusion
from 10 different tumor types and 19 histology types [51,52] . The ORR was notable, with 57% of patients
demonstrating a response. Among the responders, 7% achieved complete response (CR) and 50% had PR.
The median DOR was estimated to be 10 months, indicating a sustained and meaningful clinical benefit.
However, it is essential to acknowledge some limitations of the studies analyzed. The data presented in this
summary were based on a specific patient population and may not be generalizable to all patients with
NTRK fusion-positive ICC. Further investigations are needed to evaluate the efficacy of these targeted
therapies in larger cohorts and diverse patient populations.

Previous studies involving immune checkpoint blockade showed modest response rates of 10%-20% in
refractory ICC, but these results did not result in regulatory approval for the treatment [53,54] . However, the
[14]
TOPAZ-1 trial has reignited enthusiasm in this area . This study compared GEMCIS plus durvalumab
versus GEMCIS plus placebo. The trial results revealed that the addition of durvalumab resulted in
improved outcomes compared to the placebo group. The addition of durvalumab to GEMCIS resulted in an
OS of 12.8 months, which was longer than the OS of 11.5 months for GEMCIS alone (P = 0.021). The
median PFS was 7.2 months in the durvalumab arm compared to 5.7 months in the GEMCIS arm (P =
0.001). The ORR was 26.7% in the durvalumab arm and 18.7% in the GEMCIS arm. Although the absolute
differences in these survival endpoints are relatively small, the tail of the survival curves suggests that a
significant proportion of patients (up to 25%) were alive at 2 years and experienced durable responses,
which is unprecedented with traditional cytotoxic therapy.

KRAS has recently gained significant attention for its therapeutic development in multiple kinds of
tumors [55-57] . In a cohort study conducted by our team, which involves a collective of 1024 individuals
diagnosed with ICC, 14 different subcategories of KRAS mutations were identified, impacting 127
[58]
individuals (12.4%) . Among the identified KRAS variants, the most common was G12D, accounting for
55 cases (43.3%). This was subsequently G12V with 25 cases (19.7%), G12C with 9 cases (7.1%), and G13D
with 8 cases (6.3%). Being one of the most prevalent driver mutations in cancer, KRAS holds significant
importance in the development and advancement of tumors [59,60] . In the past, KRAS has long been
considered an "undruggable" target due to its essential role in normal cell functioning and the toxicity
associated with inhibiting its activity . Nevertheless, recent advancements have rekindled hope, as the FDA
[59]
approval of sotorasib for KRAS G12C mutations in non-small cell lung cancer (NSCLC) signifies a
breakthrough in KRAS-targeted therapy [61,62] . These achievements have sparked renewed interest in
exploring KRAS as a therapeutic target in ICC and offer potential avenues for novel treatment strategies.

A comprehensive overview of the trials, medications, and effectiveness of other inhibitors is provided in
Table 3.