BOSTON – The investigational antiangiogenic drug brivanib failed to achieve noninferiority to sorafenib in a phase III trial testing the two for first-line treatment of advanced hepatocellular carcinoma.
There is an unmet medical need for more effective and better tolerated drugs for the first-line treatment of advanced hepatocellular carcinoma (HCC) than sorafenib (Nexavar), the only drug approved by the Food and Drug Administration for the indication. In particular, in Asian-Pacific and sub-Saharan countries where HCC is most prevalent, "many patients have such advanced disease at diagnosis that potentially curative treatments are no longer available," Dr. Philip Johnson said at the annual meeting of the American Association for the Study of Liver Diseases.
He and his colleagues randomized 1,155 patients to double-blind treatment with either sorafenib, a multitargeted kinase inhibitor, or brivanib, a dual vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) receptors inhibitor. Both receptors are known to play a role in tumor growth, survival, and metastasis through proangiogenic signaling in HCC tumor cells.
The patients in this multicenter study, who had not yet received any systemic therapy, had a mean age of about 60 years, and most were men (84%). About two-thirds of the patients were Asian, and 92% were in Child-Pugh class A. The groups had a similar prevalence of infection with hepatitis B (20%) or hepatitis C (45%) viruses and alcoholic liver disease (16%).
The trial, known as the BRISK-FL study, had a hybrid noninferiority/superiority design in which the investigators set a noninferiority upper margin of 1.08, which equates to no more than a 3-week difference in median overall survival. This ensured that the risk of dying while taking brivanib was not unacceptably higher than with sorafenib, explained Dr. Johnson, professor of oncology and translational research and director of the Cancer Research U.K. Clinical Trials Unit at the University of Birmingham in England.
Based on the sample size, a noninferiority upper margin of 1.08 meant that the estimated hazard rate had to be 0.94 at highest for brivanib to be considered noninferior to sorafenib. Comparisons of the median overall survival between the groups showed an overall hazard ratio of 1.07 for brivanib with an upper 95% confidence interval value of 1.23, which was higher than the predetermined limit for noninferiority of 1.08 or less.
Median overall survival was 9.9 months with sorafenib and 9.5 months with brivanib. No subgroup of patients had better survival with either drug. The median time-to-progression was nearly equal in patients treated with sorafenib (4.1 months) and brivanib (4.2 months). Rates of complete, partial, and overall response, as well as disease control, were all similar between the groups.
A 50% or greater reduction in the level of alpha-fetoprotein occurred in 31% of 270 patients taking sorafenib and in 58% of 250 patients taking brivanib. A decline in alpha-fetoprotein levels has been considered an indication of tumor cells killed, Dr. Johnson said.
Similar percentages of patients in each group had dose reductions or underwent poststudy treatments. Both groups had similar rates of study discontinuation; the most frequent reasons were disease progression and drug toxicity.
Both agents also had similar rates of overall adverse events, but brivanib-treated patients experienced significantly higher rates of decreased appetite, fatigue, hypertension, nausea, vomiting, and hyponatremia. The adverse events that occurred more often among sorafenib-treated patients included hand-foot skin reaction, alopecia, and rash.
Both groups showed declines in quality of life at 12 weeks on the physical and role functions measured by the EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer’s Quality of Life Questionnaire–Core 36). Small, but statistically significantly greater declines in these functions in the brivanib arm have unknown clinical significance, Dr. Johnson said.
The developer of brivanib, Bristol-Myers Squibb, funded the trial. No disclosures were available for Dr. Johnson.