Linifanib Versus Sorafenib in Patients With Advanced Hepatocellular Carcinoma: Results of a Randomized Phase III Trial

J Clin Oncol. 2015 Jan 10;33(2):172-9. doi: 10.1200/JCO.2013.54.3298. Epub 2014 Dec 8.

Abstract

Purpose: This open-label phase III trial evaluated efficacy and tolerability of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC) without prior systemic therapy.

Patients and methods: Patients were randomly assigned in a 1:1 ratio to linifanib 17.5 mg once daily or sorafenib 400 mg twice daily. Patients were stratified by region (Outside Asia, Japan, and rest of Asia), Eastern Cooperative Oncology Group performance score (ECOG PS; 0 or 1), vascular invasion or extrahepatic spread (yes or no), and hepatitis B virus (HBV) infection (yes or no). The primary end point of the study was overall survival (OS). Secondary end points were time to progression (TTP) and objective response rate (ORR) per RECIST v1.1.

Results: We randomly assigned 1,035 patients (median age, 60 years; Asian, 66.6%; ECOG PS 0, 65.2%; HBV, 49.1%; vascular invasion or extrahepatic spread, 70.1%). Median OS was 9.1 months on the linifanib arm (95% CI, 8.1 to 10.2) and 9.8 months on the sorafenib arm (95% CI, 8.3 to 11.0; hazard ratio [HR], 1.046; 95% CI, 0.896 to 1.221). For prespecified stratification subgroups, OS HRs ranged from 0.793 to 1.119 and the 95% CI contained 1.0. Median TTP was 5.4 months on the linifanib arm (95% CI, 4.2 to 5.6) and 4.0 months on the sorafenib arm (95% CI, 2.8 to 4.2; HR, 0.759; 95% CI, 0.643 to 0.895; P = .001). Best response rate was 13.0% on the linifanib arm versus 6.9% on the sorafenib arm. Grade 3/4 adverse events (AEs); serious AEs; and AEs leading to discontinuation, dose interruption, and reduction were more frequent with linifanib (all P < .001).

Conclusion: Linifanib and sorafenib had similar OS in advanced HCC. Predefined superiority and noninferiority OS boundaries were not met for linifanib and the study failed to meet the primary end point. TTP and ORR favored linifanib; safety results favored sorafenib.

Trial registration: ClinicalTrials.gov NCT01009593.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / etiology
  • Carcinoma, Hepatocellular / pathology
  • Drug Administration Schedule
  • Female
  • Hand-Foot Syndrome / etiology
  • Humans
  • Hypertension / chemically induced
  • Indazoles / administration & dosage
  • Indazoles / adverse effects
  • Indazoles / therapeutic use*
  • Kaplan-Meier Estimate
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / etiology
  • Liver Neoplasms / pathology
  • Male
  • Middle Aged
  • Niacinamide / administration & dosage
  • Niacinamide / adverse effects
  • Niacinamide / analogs & derivatives*
  • Niacinamide / therapeutic use
  • Odds Ratio
  • Phenylurea Compounds / administration & dosage
  • Phenylurea Compounds / adverse effects
  • Phenylurea Compounds / therapeutic use*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / therapeutic use*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Risk Factors
  • Sorafenib
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Indazoles
  • N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N1-(2-fluoro-5-methylphenyl)urea
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Niacinamide
  • Sorafenib
  • Receptor Protein-Tyrosine Kinases

Associated data

  • ClinicalTrials.gov/NCT01009593