The experimental cancer drug brivanib did not lengthen
overall survival for patients with hepatocellular carcinoma, but it did
increase time to progression, demonstrating that it had anti-tumour activity,
researchers reported at the 47th International Liver Congress (EASL 2012) last
week in Barcelona.
years or decades chronic hepatitis B or C infection
– as well as heavy alcohol
consumption, hereditary liver diseases and other causes
– can lead to advanced
liver damage including cirrhosis and hepatocellular carcinoma (HCC), a type of
is often not detected until advanced stages and is difficult to treat.
Sorafenib (Nexavar) is the only drug
shown to improve survival in people with HCC who are not eligible for surgical
removal, but some people are unable to tolerate it.
Llovet from the University
of Barcelona and Mount Sinai School of Medicine and an international
team of colleagues conducted a phase III trial to compare brivanib versus
placebo in people with liver cancer who were unable to take or progressed despite
Brivanib is a
selective tyrosine kinase inhibitor of vascular endothelial growth factor
receptor and fibroblast growth factor receptor that demonstrated promising
evidence of efficacy in phase II studies.
The BRISK-PS trial
enrolled 395 HCC patients in Europe (42%), Asia (41%) and the Americas (17%).
Most (about 85%) were men and the median age was just over 60 years. All had
tried sorafenib for at least 14 days, but had used no other systemic
Nearly 40% had liver
cancer secondary to hepatitis B, almost 30% had hepatitis C and about 25% had
alcoholic liver disease. About 85% had advanced BCLC stage C HCC and two-thirds
had metastasis; patients randomised to receive brivanib were more likely to
have microvascular invasion of tumours into blood vessels. They generally did
not have severely impaired liver function, however, with more than 90% at
Child-Pugh stage A.
randomly assigned (2:1) to receive 800mg once-daily oral brivanib or placebo
along with the best supportive care. They were followed until they experienced
disease progression or unacceptable toxicity.
The primary endpoint
was overall survival, but the researchers also looked at other outcomes
including time to cancer progression, "disease control rate",
"objective response rate", and safety.
Brivanib did not
provide an overall improvement in survival, the investigators found. The median
length of overall survival was 9.4 months for
brivanib recipients versus 8.2 months in the placebo arm, which was not a
significant difference (p = 0.33).
Further, no differences in overall survival were
identified for any pre-specified subgroups stratified by type of liver disease,
degree of functional disability, tumour size, blood vessel invasion and spread
of cancer outside the liver, and whether they were non-responsive to or
intolerant of sorafenib.
Although the primary endpoint was not met, secondary
endpoints showed improvement. About 6% of brivanib recipients and 14% of
placebo recipients died within 30 days after the last treatment dose. Time to
progression was significantly longer in the brivanib group compared with the
placebo group (4.2 vs 2.7 months; p = 0.0001). Brivanib recipients were six times
more likely to demonstrate partial response (12 vs 2%) and half as likely to
experience disease progression (22 vs 44%).
Almost all participants experienced adverse events,
and most had serious adverse events, but these proportions were similar in the
brivanib and placebo arms (63% and 57%, respectively, for serious adverse
events). However, brivanib recipients were more likely to experience several
events including decreased appetite, fatigue, high blood pressure and
gastrointestinal symptoms. Investigators judged six deaths in the brivanib arm
to be possibly related to the study drug.
The researchers concluded that while "the primary
endpoint of improved overall survival was not met...there were improvements in
time to progression, disease control rate and objective response rate,
indicating anti-tumour activity of brivanib". They added that
"brivanib had an acceptable safety profile".
In a overview of liver cancer research on the final
day of the congress, Jordi Bruix from the University
of Barcelona noted that while brivanib did not
demonstrate a significant survival advantage in BRISK, it did delay tumour
progression, raising the question of what types of response should be measured.
Further studies of brivanib are currently underway.