Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: Analysis of two phase III studies
Journal
Journal of Hepatology
Journal Volume
67
Journal Issue
5
Pages
999-1008
Date Issued
2017
Author(s)
Abstract
Background & Aims: Sorafenib, an oral multikinase inhibitor, significantly prolonged overall survival (OS) vs. placebo in patients with unresectable hepatocellular carcinoma (HCC) in two phase III studies, SHARP (Sorafenib HCC Assessment Randomized Protocol) and Asia Pacific (AP). To assess prognostic factors for HCC and predictive factors of sorafenib benefit, we conducted a pooled exploratory analysis from these placebo-controlled phase III studies. Methods: To identify potential prognostic factors for OS, univariate and multivariate (MV) analyses were performed for baseline variables by Cox proportional hazards model. Hazard ratios (HRs) and median OS were evaluated across pooled subgroups. To assess factors predictive of sorafenib benefit, the interaction term between treatment for each subgroup was evaluated by Cox proportional hazard model. Results: In 827 patients (448 sorafenib; 379 placebo) analyzed, strong prognostic factors for poorer OS identified from MV analysis in both treatment arms were presence of macroscopic vascular invasion (MVI), high alpha-fetoprotein (AFP), and high neutrophil-to-lymphocyte ratio (NLR; ? vs. >median [3.1]). Sorafenib OS benefit was consistently observed across all subgroups. Significantly greater OS sorafenib benefit vs. placebo was observed in patients without extrahepatic spread (EHS; HR, 0.55 vs. 0.84), with hepatitis C virus (HCV) (HR, 0.47 vs. 0.81), and a low NLR (HR, 0.59 vs. 0.84). Conclusions: In this exploratory analysis, presence of MVI, high AFP, and high NLR were prognostic factors of poorer OS. Sorafenib benefit was consistently observed irrespective of prognostic factors. Lack of EHS, HCV, and lower NLR were predictive of a greater OS benefit with sorafenib. Lay summary: This exploratory pooled analysis showed that treatment with sorafenib provides a survival benefit in all subgroups of patients with HCC; however, the magnitude of benefit is greater in patients with disease confined to the liver (without extrahepatic spread), or in those with hepatitis C virus, or a lower neutrophil-to-lymphocyte ratio, an indicator of inflammation status. These results help inform the prognosis of patients receiving sorafenib therapy and provide further refinements for the design of trials testing new agents vs. sorafenib. Clinical Trial Numbers: NCT00105443 and NCT00492752. ? 2017 European Association for the Study of the Liver
Subjects
Hepatocellular carcinoma; Overall survival; Predictive; Prognostic; Sorafenib
SDGs
Other Subjects
alpha fetoprotein; sorafenib; alpha fetoprotein; antineoplastic agent; carbanilamide derivative; nicotinamide; sorafenib; adult; aged; Article; cancer prognosis; cancer survival; female; hepatitis C; human; liver cell carcinoma; major clinical study; male; metastasis; neutrophil lymphocyte ratio; overall survival; phase 3 clinical trial (topic); priority journal; retrospective study; treatment outcome; analogs and derivatives; blood; clinical trial; controlled study; leukocyte count; liver cell carcinoma; liver tumor; lymphocyte; middle aged; neutrophil; pathology; phase 3 clinical trial; predictive value; procedures; prognosis; randomized controlled trial; tumor invasion; alpha-Fetoproteins; Antineoplastic Agents; Carcinoma, Hepatocellular; Female; Humans; Leukocyte Count; Liver Neoplasms; Lymphocytes; Male; Middle Aged; Neoplasm Invasiveness; Neutrophils; Niacinamide; Phenylurea Compounds; Predictive Value of Tests; Prognosis
Publisher
Elsevier B.V.
Type
journal article