Biomarker analyses of clinical outcomes in patients with advanced hepatocellular carcinoma treated with Sorafenib with or without Erlotinib in the SEARCH Trial

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Zhu, Andrew X. ; Kang, Yoon-Koo ; Rosmorduc, Olivier ; Evans, T.R. Jeffrey ; Santoro, Armando ; Ross, Paul ; Gane, Edward ; Vogel, Arndt ; Jeffers, Michael ; Meinhardt, Gerold ; Peña, Carol E.A. (2016)

Purpose: Sorafenib is the current standard therapy for advanced HCC, but validated\ud biomarkers predicting clinical outcomes are lacking. This study aimed to identify biomarkers\ud predicting prognosis and/or response to sorafenib, with or without erlotinib, in HCC patients from\ud the phase 3 SEARCH trial.\ud Experimental Design: 720 patients were randomized to receive oral sorafenib 400 mg BID plus\ud erlotinib 150 mg QD or placebo. Fifteen growth factors relevant to the treatment regimen and/or\ud to HCC were measured in baseline plasma samples.\ud Results: Baseline plasma biomarkers were measured in 494 (69%) patients (sorafenib plus\ud erlotinib, n=243; sorafenib plus placebo, n=251). Treatment arm–independent analyses showed\ud that elevated HGF (HR, 1.687 [high vs low expression]; endpoint multiplicity adjusted [e-adj]\ud P=0.0001) and elevated plasma VEGF-A (HR, 1.386; e-adj P=0..0377) were significantly\ud associated with poor OS in multivariate analyses, and low plasma KIT (HR, 0.75 [high vs low];\ud P=0.0233; e-adj P=0.2793) tended to correlate with poorer OS. High plasma VEGF-C\ud independently correlated with longer TTP (HR, 0.633; e-adj P=0.0010) and trended toward\ud associating with improved disease control rate (univariate:OR, 2.047; P=0.030; e-adj P=0.420).\ud In 67% of evaluable patients (339/494), a multimarker signature of HGF, VEGF-A, KIT, epigen,\ud and VEGF-C correlated with improved median OS in multivariate analysis (HR, 0.150;\ud P<0.00001). No biomarker predicted efficacy from erlotinib.\ud Conclusions: Baseline plasma HGF, VEGF-A, KIT, and VEGF-C correlated with clinical\ud outcomes in HCC patients treated with sorafenib with or without erlotinib. These biomarkers\ud plus epigen constituted a multimarker signature for improved OS.
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