Biliary tract cancer is a relatively rare malignancy globally but nowadays the instance of BTC is
increasing. The prognosis of advanced biliary tract cancer is poor; there are many reasons but one of
the reasons is limited treatment options. Especially the first line standard of care for advanced BTC is
gemcitabine and cisplatin combination chemotherapy which has been unchanging for over a decade.
Biologically, actually BTC has an immunogenic feature so might be a good candidate for
immunotherapy, however, so far immune checkpoint inhibitor monotherapy has shown very modest
efficacy in general in biliary tract cancer. In contrast, previously we conducted a phase II study using
gemcitabine cisplatin chemotherapy and a PD-L1 inhibitor, durvalumab, and a CTLA-4 inhibitor
altogether. We found that with this combination the efficacy is quite promising and the safety profile is
quite acceptable.
So based on this we launched this TOPAZ-1 global phase III study to test the hypothesis that a
chemotherapy and immunotherapy combination will be better than chemotherapy alone that is current
standard of care in advanced biliary tract cancer.
What was the methodology used in this study?
TOPAZ-1 is actually the global study and it is a randomised double-blind placebo-controlled study. It
was conducted in a global scope, not a single country or single region, it is a global study. The
patients were included and randomised to the durvalumab plus gemcitabine cisplatin combination arm
or placebo plus gemcitabine cisplatin combination arm in a one-to-one ratio. The primary endpoint in
this TOPAZ-1 study is overall survival. We have a single primary endpoint here. Of course, there are
several secondary endpoints which included progression free survival, objective response rate and
safety, something like that.
What were the key findings?
The most important finding is that the overall survival was improved by adding durvalumab on top of
gemcitabine cisplatin. The hazard ratio was 0.80 so it means that by adding durvalumab onto
gemcitabine cisplatin chemotherapy we can reduce the death risk by 20%.
That is a key finding and not only the overall survival but also all secondary efficacy parameters have
shown improvement by the addition of durvalumab, like progression free survival also improved
significantly and objective response rate was increased. Time to response was also quicker with
durvalumab and duration of response is also better in the durvalumab arm.
In parallel with this efficacy another important finding is the safety profile. Actually we have three
drugs here but the safety profile is quite similar between the two arms. So adverse events and
treatment related adverse events and grade 3/4 adverse events also were observed at a very similar
frequency between the two arms. So it means that we can improve the patient survival efficacy by
adding no more toxicity to the current standard of care.
How can these results impact the future treatment of advanced biliary tract cancer?
At this time, as I mentioned, the current standard of care is gemcitabine cisplatin; that is the global
standard of care, actually, for first line advanced biliary tract cancer. This TOPAZ-1 is the first phase
III study which is a global phase III study to show the overall survival benefit compared to a
gemcitabine cisplatin regimen. So it’s quite meaningful so we believe this durvalumab plus
gemcitabine cisplatin could be a new standard of care in this setting, first line, advanced biliary tract
cancer.
This result will have practice changing implications globally, we believe.
Actually this is the first success of immunotherapy in the biliary tract cancer field, so a positive result
in a phase III study using immunotherapy. This is the first success of immunotherapy in biliary tract
cancer. So this is the starting point for more immunotherapy drug development in biliary tract cancer.
From now on I believe more and more clinical trials using very interesting immunotherapeutic agents
will be investigated in this biliary tract cancer field.
