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Background: Second-line therapy for advanced NSCLC patients(pts)after progression on platinum-based regimens typically employs CT or E.Improved PFS in E-treated pts is associated with EGFR sensitizing mutations.However,a test for optimizing treatment in pts with wild-type or unknown EGFR mutation status or squamous histology is of clinical value.VeriStrat(VS)is a serum protein test that assigns "good"(VSG)or "poor"(VSP)classification and has demonstrated prognostic and predictive utility.PROSE is a multicenter prospective randomized biomarker validation trial,designed to evaluate the ability of VS to predict survival in second-line NSCLC pts treated with E or CT.It is the first completed prospective randomized biomarker validation trial following the MARVEL design(Freidlin et al.JNCI.2010).Methods: 285 pts,stratified by ECOG-PS,smoking,and blinded pretreatment VS classification,were randomized 1:1 to receive E or CT at standard doses.Primary endpoint was overall survival(OS)and the primary hypothesis was significant interaction between VS status and treatment.Sample size was calculated based on an estimated 65%/35%VSG:VSP ratio and hazard ratio(HR)for interaction of 2.35,with a 2-sided α=0.05 and 90%power.Results: 285 pts were randomized and 263(129 CT,134 E)included in the per protocol primary analysis.68%of pts in CT arm and 72%in E arm were classified as VSG.Analysis was performed at 226 events.The trial reached its primary objective of significant interaction between treatment and VeriStrat classification with an interaction p value of 0.037.Pts in the VSP group performed worse on E compared to CT(HR: 1.72,95%CI: 1.08-2.74); there was no significant difference in OS between treatments in the VSG group(HR: 1.09,95%CI:0.79-1.50).194/198 pts with histologic diagnosis had tissue available for EGFR and KRAS mutations.Conclusions: The results suggest that VS status is predictive of differential OS benefit for E versus CT in second line setting,complementing the result from a retrospective analysis of NCIC BR.21 where the prognostic behavior of VS was established(Carbone et al.JTO.2012).