No Overall Survival Benefit With Brivanib in Advanced Hepatocellular Carcinoma Patients After Sorafenib Failure or Intolerance
The investigational agent brivanib is a selective dual inhibitor of VEGF and fibroblast growth factor receptors, both implicated in hepatocellular carcinoma. In a trial (BRISK-PS) reported in Journal of Clinical Oncology, Josep M. Llovet, MD, of the Icahn School of Medicine at Mount Sinai in New York and colleagues compared brivanib vs placebo plus best supportive care in patients with advanced hepatocellular carcinoma who had shown disease progression despite or were intolerant of sorafenib (Nexavar) treatment. The study showed that brivanib did not improve overall survival, although benefits in response rate and time to progression were observed.
Study Details
In this multinational phase III trial—the first phase III trial in patients who have already received sorafenib—395 patients with advanced hepatocellular who progressed on/after or were intolerant of sorafenib were randomly assigned (2:1) to receive oral brivanib at 800 mg once daily plus best supportive care (n = 263) or placebo plus best supportive care (n = 132). The primary endpoint was overall survival.
Overall, 42% of patients were from Europe, 41% from Asia, and 17% from the Americas. Baseline characteristics were generally balanced between the brivanib and placebo groups, except for greater proportions of brivanib patients with macrovascular invasion (31% vs 25%) and portal vein invasion and/or thrombosis (18% vs 12%) and a higher alpha-fetoprotein level in brivanib patients (median, 204 vs 100 ng/mL). Most patients had progression on prior sorafenib (87%) and one or more known risk factors for hepatocellular carcinoma (84%), including hepatitis B (37%), hepatitis C (27%), and alcoholic liver disease (25%). Most patients had Barcelona Clinic Liver Cancer stage C (86%) with preserved liver function (Child-Pugh Class A in 92%) and good Eastern Cooperative Oncology Group performance status (0 in 59%).
Study treatment was discontinued in 90% of brivanib patients and 92% of placebo patients, with the most common reasons being disease progression (50% and 70%) and study drug toxicity (23% and 7%). Median treatment duration was 3.1 months for brivanib and 2.5 months for placebo. After discontinuation of study treatment, 27% of the brivanib group and 35% of the placebo group received systemic therapies and 18% and 20% received nonsystemic treatments.
Overall Survival Outcome
Overall survival was not significantly improved in the brivanib vs placebo group (hazard ratio [HR] = 0.89, 95.8% confidence interval [CI] = 0.69–1.15, P = .331); median overall survival was 9.4 and 8.2 months, respectively. Overall survival results across prespecified subgroups were generally consistent with the primary overall survival analysis. On multivariate analysis, alpha-fetoprotein (< 200 ng/mL vs ≥ 200 g/mL, P < .001) and portal vein invasion (no vs yes, P < .001) were significant prognostic factors for overall survival. After adjustment for all prespecified factors, the hazard ratio for overall survival for brivanib vs placebo was 0.81 (P = .1044). Post hoc analyses using poststudy treatments as a time-dependent covariate did not show an impact of poststudy treatment on overall survival.
Secondary Endpoints
Time to progression was significantly longer in the brivanib group (median 4.2 vs 2.7 months, HR = 0.56, P < .001), including after adjustment for baseline prognostic factors (HR = 0.56, 95% CI = 0.42–0.76). The objective response rate was also significantly higher with brivanib treatment (10% vs 2%, odds ratio [OR] = 5.75, P = .0030), as was disease control rate (61% vs 40%, OR = 2.38, P < .001). Among patients with baseline alpha-fetoprotein greater than the upper limit of normal, a reduction of ≥ 50% from baseline occurred in 54% of brivanib patients and 7% of placebo patients.
Adverse Events
Study discontinuation due to treatment-related adverse events occurred in 23% of brivanib patients and 7% of placebo patients. The most frequent treatment-related grade 3 or 4 adverse events in the brivanib group included hypertension (17% vs 2%), fatigue (13% vs 1%), hyponatremia (11% vs 2%), and decreased appetite (10% vs 2%). The most frequent grade 3 or 4 laboratory abnormalities were hyponatremia (27% vs 14%), AST increase (27% vs 24%), and hyperbilirubinemia (21% vs 18%). Six deaths on study were considered by investigators as possibly related to treatment, all of which were in the brivanib arm and occurred within 30 days of the final dose. Two of the deaths were a result of encephalopathy, and one each was due to liver failure, acidosis, sudden death, and coma/cerebral edema.
The investigators concluded: “In patients with [hepatocellular carcinoma] who had been treated with sorafenib, brivanib did not significantly improve [overall survival]. The observed benefit in the secondary outcomes of [time to progression] and objective response rate warrants further investigation…. The results of our trial may inform the design of future studies in this patient population.”
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®.
