First-Line Brivanib Not Noninferior to Sorafenib in Advanced Hepatocellular Carcinoma
The investigational drug brivanib is a dual inhibitor of VEGF and fibroblast growth factor signaling, both implicated in hepatocellular carcinoma. In a noninferiority trial (BRISK-FL) reported in Journal of Clinical Oncology, Philip J. Johnson, MD, of the Institute of Translational Medicine, University of Liverpool, and colleagues compared first-line brivanib vs sorafenib (Nexavar) in patients with unresectable advanced hepatocellular carcinoma. Brivanib did not meet the criterion for noninferiority in overall survival compared with sorafenib.
Study Details
In the multinational phase III trial, 1,155 patients with no prior systemic therapy were randomly assigned to oral sorafenib at 400 mg twice daily (n = 578) or oral brivanib at 800 mg once daily (n = 577). The primary endpoint was overall survival.
In total, 62% of patients were from Asia, 23% from Europe, 13% from the Americas, 0.8% from Australia, and 0.6% from Africa. The treatment groups were well matched for baseline characteristics. Most patients had Barcelona Clinical Liver Cancer stage C (77%), Child-Pugh A disease (92%), and good Eastern Cooperative Oncology Group performance status (0 in 62%). Risk factors for hepatocellular carcinoma were hepatitis B virus infection (44%), hepatitis C virus infection (20%), and alcohol use (16%).
A total of 1,150 patients were treated (per-protocol population). At the time of the final analysis, 6% of the brivanib group and 11% of the sorafenib group remained on study. The most common reasons for study discontinuation were disease progression (46% in the brivanib group and 53% in the sorafenib group) and study drug toxicity (24% and 15%). Median duration of treatment was 3.2 months in the brivanib group and 4.1 months in the sorafenib group. Post-study systemic treatments were received by 22% of the brivanib group and 21% of the sorafenib group, and nonsystemic treatments were received by 19% and 17%.
Overall Survival
The primary endpoint of overall survival noninferiority for brivanib vs sorafenib in the per-protocol population was not met (hazard ratio [HR] = 1.06, 95.8% confidence interval [CI] = 0.93–1.22, P = .373), based on the prespecified noninferiority margin (upper CI limit for HR ≤ 1.08). Median overall survival was 9.5 months in the brivanib group and 9.9 months in the sorafenib group. Overall survival results were similar in the intent-to-treat population (HR = 1.07, 95.8% CI = 0.94–1.23, P = .312). Results for subgroups were consistent with those for the overall study population. On multivariate analysis, significant prognostic factors for overall survival were alpha-fetoprotein, tumor morphologic features, size of the largest nodule, Child-Pugh score, and major portal vein invasion. After adjusting for these factors, the effect of brivanib vs sorafenib remained unchanged (HR = 1.09, 95% CI = 0.95–1.25).
Secondary Endpoints
Median time to progression was 4.2 months in the brivanib group and 4.1 months in the sorafenib group (P = .853), objective response rate was 12% vs 9% (P = .057), and disease control rate was 66% vs 65% (P = .874). Among patients with baseline alpha-fetoprotein ≥ 200 ng/mL and at least one on-study alpha-fetoprotein assessment, alpha-fetoprotein reduction of ≥ 50% from baseline was observed in 58% of brivanib patients vs 31% of sorafenib patients. Similar reductions were observed when the baseline cutoff used was the upper limit of normal or 400 ng/mL.
Adverse Events
Among adverse events of any grade, hand-foot skin reaction, alopecia, rash, and pyrexia were more frequent in sorafenib patients, and decreased appetite, fatigue, hypertension, nausea, vomiting, hyponatremia, headache, dysphonia, and dizziness were more frequent in brivanib patients. Diarrhea, abdominal pain, constipation, hyperbilirubinemia, elevated AST, elevated ALT, and weight loss occurred at a similar rate in the two groups. The most frequent grade 3 or 4 adverse events were hyponatremia (23% in brivanib group vs 9% in sorafenib group), AST elevation (14% vs 17%), fatigue (15% vs 7%), hand-foot skin reaction (2% vs 15%), and hypertension (13% vs 5%).
Treatment was discontinued due to adverse events in 43% of brivanib patients and 33% of sorafenib patients, with the most common reasons being fatigue (5%), hyponatremia (2%), decreased appetite (2%), hyperbilirubinemia (2%), and AST elevations (2%) in the brivanib group and hyperbilirubinemia (3%) and AST elevations (2%) in the sorafenib group. Dose reduction occurred in 49% and 50% of patients, and dose interruption occurred in 58% of both groups.
The investigators concluded: “[T]his study did not meet its primary [overall survival] objective in the first-line treatment of advanced [hepatocellular carcinoma], based on a noninferiority statistical design, but it did show similar antitumor activity for brivanib and sorafenib, based on time to progression, objective response rate, and disease control rate. Brivanib had an acceptable safety profile; however, it was less well-tolerated than sorafenib.”
The study was supported by Bristol-Myers Squibb.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
