9045 Background: Gene expression profiling by microarrays was used to identify markers predictive of the clinical activity of the MAGE-A3 Antigen-Specific Cancer Immunotherapeutic (ASCI) recorded in a phase II study in metastatic melanoma. Methods: 75 patients with progressive, unresectable stage III or stage IV M1a MAGE-A3 (+) melanomas, were randomized as 1st-line therapy between immunization with MAGE-A3 protein combined with GSK proprietary Adjuvant Systems AS15 or AS02B. Gene expression profiling was performed on tumor biopsies taken prior to any immunization. Results: Initial analysis using supervised hierarchical clustering of 2 objective responders (OR) with 7 non-responders identified 2 gene clusters based on differential expression. The correlation of this gene expression signature (GS) and objective response was further confirmed on 22 patients. Interestingly, mixed response (MR) and stable disease > 6 months (SD) clustered with OR, suggesting a strong association between the identified signature and the MAGE-A3 induced clinical benefit. Independent validation on additional 30 patients confirmed the association of clinical benefit and the molecular signature. Most of the identified genes are immune-related, defining a particular biological context present in the tumor environment before immunization. The signature was randomly distributed in the 2 study arms and identified all patients with clinical benefit (OR, MR, SD). The AS15 arm has shown to induce a higher MAGE-A3 immune response and more frequent clinical activity. The predictive signature improves significantly the median time to treatment failure (2.3 months in the GS (-) and 10.3 months in the GS (+) population (HR = 0.31; 95% CI: 0.13–0.76). Conclusions: The gene expression in metastatic melanoma reported here is strongly correlated with a clinical response to the MAGE-A3 ASCI treatment. This signature reflects an immune microenvironment in the tumor present prior to any therapeutic intervention following MAGE-A3 ASCI administration. Such molecular signature could be used to select patients with a higher likelihood of clinical response the MAGE-A3 ASCI. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline Biologicals GlaxoSmithKline Biologicals