Biomarker analyses of clinical outcomes in patients with advanced hepatocellular carcinoma treated with Sorafenib with or without Erlotinib in the SEARCH Trial
Purpose: Sorafenib is the current standard therapy for advanced HCC, 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 HCC patients from
the phase 3 SEARCH trial.
Experimental Design: 720 patients were randomized to receive oral sorafenib 400 mg BID plus
erlotinib 150 mg QD or placebo. Fifteen growth factors relevant to the treatment regimen and/or
to HCC 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 HGF (HR, 1.687 [high vs low expression]; endpoint multiplicity adjusted [e-adj]
P=0.0001) and elevated plasma VEGF-A (HR, 1.386; e-adj P=0..0377) were significantly
associated with poor 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 VEGF-C
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, VEGF-A, KIT, epigen,
and VEGF-C correlated with improved median OS in multivariate analysis (HR, 0.150;
P<0.00001). No biomarker predicted efficacy from erlotinib.
Conclusions: Baseline plasma HGF, VEGF-A, KIT, and VEGF-C correlated with clinical
outcomes in HCC patients treated with sorafenib with or without erlotinib. These biomarkers
plus epigen constituted a multimarker signature for improved OS
