Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial

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.

Fig 1.

CONSORT diagram. AE, adverse event; PD, progressive disease.

Fig 2.

Kaplan-Meier analysis of overall survival with a cutoff point at the 667th patient death. HR, hazard ratio.

Fig 3.

Analysis of overall survival by prespecified stratification subgroups, per interactive voice response system for stratification factors. ECOG, Eastern Cooperative Oncology Group; EHS, extrahepatic spread; HR, hazard ratio; mo, months; VI, vascular invasion.

Fig 4.

Kaplan-Meier analysis of time to progression. HR, hazard ratio.

Fig A1.

Analysis of time to progression by prespecified stratification subgroups, per interactive voice response system for stratification factors. ECOG, Eastern Cooperative Oncology Group; EHS, extrahepatic spread; HR, hazard ratio; mo, months; VI, vascular invasion.