No Overall Survival Difference for Linifanib vs Sorafenib in Advanced Hepatocellular Carcinoma


Key Points

  • There was no overall survival difference for linifanib vs sorafenib.
  • Linifanib was associated with prolonged time to progression and greater toxicity.

In a phase III trial reported in the Journal of Clinical Oncology, Cainap et al found that treatment with linifanib, an ATP-competitive inhibitor of VEGF and PDGF receptor tyrosine kinases, did not improve overall survival compared with sorafenib (Nexavar) treatment in patients with advanced hepatocellular carcinoma who had not received prior systemic therapy.

Study Details

In the open-label trial, conducted primarily in Asian patients, 1,035 patients were randomly assigned to receive linifanib at 17.5 mg once daily (n = 514) or sorafenib at 400 mg twice daily (n = 521). Stratification factors included region (outside Asia, Japan, and rest of Asia), Eastern Cooperative Oncology Group performance status (0 or 1), and hepatitis B virus (HBV) infection.

Patients had a median age of 60 years; most were male (84.6%), Asian (66.6%), had HBV infection (53.2%), Child-Pugh Class A liver function (94.4%), performance status of 0 (64.4%), and Barcelona Clinic Liver Cancer stage C disease (82.3%). The primary endpoint was overall survival. 

Early Closure

After enrollment was complete, analysis of data by an independent data monitoring committee resulted in the recommendation to stop the trial for futility to show superiority (hazard ratio [HR] for overall survival = 0.989, 95% confidence interval [CI] = 0.821–1.192, at 455 overall survival events). The study was amended for early closure, and 184 patients remained on treatment while subsequent therapy was planned. The current analysis is the final overall survival analysis conducted at 667 overall survival events.

Overall Survival

Median overall survival was 9.1 months in the linifanib group vs 9.8 months in the sorafenib group (HR = 1.046, 95% confidence interval [CI] = 0.896–1.221). Hazard ratios for all subgroup comparisons were nonsignificant, including those for non-Asia regions (1.108), Japan (0.793), and the rest of Asia (1.038) and for HBV-positive (0.965) and HBV-negative patients (1.113).

Median time to progression was 5.4 vs 4.0 months (HR = 0.759, P < .001), with subgroup analysis suggesting benefit of linifanib among patients in Asia (excluding Japan), those with performance status of 0, and those with HBV infection. Response was observed in 13.0% vs 6.9% of patients.

Adverse Events

Grade 3 or 4 adverse events, serious adverse events, and adverse events leading to dose interruption and reduction and treatment discontinuation were more common with linifanib (all P < .001). Grade 3 or 4 adverse events occurred in 85.3% vs 75.0% of patients, with those occurring significantly more frequently with linifanib (P < .05) consisting of hypertension (20.8% vs 10.6%), fatigue (9.6% vs 4.8%), hepatic encephalopathy (7.3% vs 3.3%), asthenia (7.1% vs 2.1%), ascites (6.1% vs 3.3%), thrombocytopenia (5.3% vs 2.1%), hypokalemia (4.7% vs 2.3%), vomiting (4.3% vs 0.8%),and hypoglycemia (3.1% vs 0.8%); grade 3 or 4 increased ALT was more common with sorafenib (4.8% vs 2.2%). Any grade bleeding occurred in 27.3% vs 17.7% (most commonly epistaxis and gingival bleeding). Serious adverse events occurred in 52.4% vs 38.5%. Adverse events led to discontinuation of treatment in 36.3% vs 25.4% and to dose reductions in 55.9% vs 40.8%.

The investigators concluded: “Linifanib and sorafenib had similar [overall survival] in advanced [hepatocellular carcinoma]. Predefined superiority and noninferiority [overall survival] boundaries were not met for linifanib and the study failed to meet the primary end point. [Time to progression] and [objective response rate] favored linifanib; safety results favored sorafenib.”

Calin Cainap, MD, of the Institute of Oncology, Cluj-Napoca, Romania, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by AbbVie. For full disclosures of the study authors, visit

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®.