The investigational cancer drug brivanib did not
significantly increase survival for people with hepatocellular carcinoma over
existing standard therapy, researchers reported at the recent Liver Meeting 2012, the 63rd Annual Meeting of the American
Association for the Study of Liver Diseases (AASLD) in Boston. But another drug, tivantinib, did appear beneficial for a subset of
Over years or decades
chronic hepatitis B or C, heavy alcohol
consumption or other causes can
lead to severe liver disease including cirrhosis and hepatocellular carcinoma
(HCC), a form of primary liver cancer. One of the most common cancers worldwide
– especially in Asia – it is often not
detected until advanced stages and is therefore difficult to treat.
The multikinase inhibitor sorafenib (Nexavar) is currently the only drug
shown to extend survival for liver cancer patients who are not eligible for
resection or surgical removal. Like many cancer drugs, however, it can be
difficult to tolerate.
Philip Johnson, from the University of
Birmingham, and an international team of colleagues conducted the phase 3 BRISK-FL trial to evaluate the safety
and efficacy of sorafenib versus brivanib, a selective inhibitor of receptors
for vascular endothelial growth factor and fibroblast growth factor, two
chemical messengers that play a role in liver cancer development. In previous
trials brivanib demonstrated anti-tumour activity, though it did not extend overall survival compared with placebo.
BRISK-FL enrolled 1155 people with advanced HCC
who had received no prior systemic treatment. Most (84%) were men, about
two-thirds were Asian and the median age was 60 years. About 45% had hepatitis
B, about 20% had hepatitis C and about 15% had alcoholic liver disease. More
than 90% were Child-Pugh stage A. Half had distant metastasis, or spread beyond
the liver, and just over one-quarter had regional lymph node metastasis.
Participants were randomly assigned to receive
800mg oral brivanib or 400mg oral sorafenib, both twice daily. They were
followed until they experienced disease progression or unacceptable toxicity.
The researchers looked at overall survival as a primary endpoint, as well as
time to progression, objective response rate, disease control rate and quality
The median duration of treatment was 3.2 months
in the brivanib arm and 4.1 months in the sorafenib arm. Median overall survival
was 9.5 months in the brivanib arm compared with 9.9 months in the sorafenib
arm, not a statistically significant difference. No significant survival
differences were seen in subgroups based on geographic region, cause of HCC or
The median time to progression was 4.2 months in
the brivanib arm compared with 4.1 months in the sorafenib arm, again not a
significant difference. Less than 1% of people in the both treatment groups
experienced complete response. Partial response was seen in 12% of patients in
the brivanib arm and 8% in the sorafenib arm. About half of participants in
both arms (54 vs 56%, respectively) had stable disease, whilst disease
progression occurred in 16 and 24%, respectively.
Objective response rates as reported by patients
were 12% in the brivanib arm and 9% in the sorafenib arm, a difference that fell
just short of statistical significance; 46% of brivanib recipients and 53% of
sorafenib recipients discontinued the study early due to disease progression.
Both brivanib and sorafenib were difficult to
tolerate, with more that half of patients in both arms experiencing serious
adverse events (59 vs 52%, respectively. Rates of adverse events leading to
treatment discontinuation were 43 and 33%, respectively. Most deaths during
the study were due to cancer progression; 1.6 vs 0.3%, respectively, in the
two treatment arms were attributed to drug toxicity.
Loss of appetite, fatigue, nausea, vomiting,
high blood pressure and low blood sodium were at least 10% more common in the
brivanib arm, whilst hair loss, rash and hand or foot skin reactions were more
common in the sorafenib arm. Patients' quality of life declined considerably in
both arms by week 12 of treatment, slightly but significantly more so in the brivanib arm.
Based on these findings the researchers
concluded: "The primary endpoint of non-inferiority in overall survival
for brivanib vs sorafenib was not met." However, they added,
"Brivanib had antitumour activity similar to sorafenib", based on
time to progression, objective response rate and disease control rate. "Brivanib
had an acceptable safety profile" but was "generally less
well-tolerated than sorafenib".
At a conference overview for the media, AASLD
president Guadalupe Garcia-Tsao
said that, since brivanib showed no improvement in survival over sorafenib but
was less well-tolerated, "sorafenib will continue to be the standard of
care for these patients".