Supplementary Figure 1. Kaplan-Meier survival curves of treatment effect on TTP in patients with low (left panel) and high (right panel) baseline levels of (A) epiregulin (max chi interaction P value = 0.193), (B) VEGF-A (max chi interaction P value = 0.153), (C) HGF (max chi interaction P value = 0.157), and (D) PDGF (max chi interaction P value = 0.167). All biomarkers were dichotomized using the max chi optimized cutoff. BL=baseline; Erlot=erlotinib; HGF=hepatocyte growth factor; PDGF=platelet-derived growth factor; Pla=placebo; Sor=sorafenib; TTP=time to progression; VEGF=vascular endothelial growth factor.
ARTICLE ABSTRACT
Purpose: Sorafenib is the current standard therapy for advanced hepatocellular carcinoma, but validated biomarkers predicting clinical outcomes are lacking. This study aimed to identify biomarkers predicting prognosis and/or response to sorafenib, with or without erlotinib, in hepatocellular carcinoma patients from the phase III SEARCH trial.Experimental Design: A total of 720 patients were randomized to receive oral sorafenib 400 mg twice daily plus erlotinib 150 mg once daily or placebo. Fifteen growth factors relevant to the treatment regimen and/or to hepatocellular carcinoma were measured in baseline plasma samples.Results: Baseline plasma biomarkers were measured in 494 (69%) patients (sorafenib plus erlotinib, n = 243; sorafenib plus placebo, n = 251). Treatment arm–independent analyses showed that elevated hepatocyte growth factor [HGF; HR, 1.687 (high vs. low expression); endpoint multiplicity adjusted (e-adj) P = 0.0001] and elevated plasma VEGFA (HR, 1.386; e-adj P = 0.0377) were significantly associated with poor overall survival (OS) in multivariate analyses, and low plasma KIT [HR, 0.75 (high vs. low); P = 0.0233; e-adj P = 0.2793] tended to correlate with poorer OS. High plasma VEGFC independently correlated with longer TTP (HR, 0.633; e-adj P = 0.0010) and trended toward associating with improved disease control rate (univariate: OR, 2.047; P = 0.030; e-adj P = 0.420). In 67% of evaluable patients (339/494), a multimarker signature of HGF, VEGFA, KIT, EPGN, and VEGFC correlated with improved median OS in multivariate analysis (HR, 0.150; P < 0.00001). No biomarker predicted efficacy from erlotinib.Conclusions: Baseline plasma HGF, VEGFA, KIT, and VEGFC correlated with clinical outcomes in hepatocellular carcinoma patients treated with sorafenib with or without erlotinib. These biomarkers plus EPGN constituted a multimarker signature for improved OS. Clin Cancer Res; 22(19); 4870–9. ©2016 AACR.
