ARTICLE ABSTRACTPurpose: Copy number alterations have been shown to be involved in melanoma pathogenesis. The randomized phase III clinical trial E2603: carboplatin, paclitaxel, ± sorafenib (CP vs. CPS) offers a large collection of tumor samples to evaluate association of somatic mutations, genomic alterations, and clinical outcomes, prior to current FDA-approved therapies.Experimental Design: Copy number and mutational analysis on 119 pretreatment samples was performed.Results: CPS therapy was associated with improved progression-free survival (PFS) compared with CP in patients with tumors with RAF1 (cRAF) gene copy gains (HR, 0.372; P = 0.025) or CCND1 gene copy gains (HR, 0.45; P = 0.035). CPS therapy was associated with improved overall survival (OS) compared with CP in patients with tumors with KRAS gene copy gains (HR, 0.25; P = 0.035). BRAF gene copy gain and MET amplification were more common in samples with V600K versus V600E mutations (P < 0.001), which was validated in The Cancer Genome Atlas (TCGA) dataset.Conclusions: We observed improved treatment response with CPS in patients with melanoma whose tumors have RAF1 (cRAF), KRAS, or CCND1 amplification, all of which can be attributed to sorafenib targeting CRAF. These genomic alterations should be incorporated in future studies for evaluation as biomarkers. Clin Cancer Res; 22(2); 374–82. ©2015 AACR.