Copy Number Changes Are Associated with Response to Treatment with Carboplatin, Paclitaxel, and Sorafenib in Melanoma

Purpose: 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. Materials and Methods: Copy number and mutational analysis on 119 pretreatment samples was performed. Results: CPS therapy was associated with improved PFS compared to 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 OS compared to 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 vs V600E mutations (P<0.001), which was validated in the TCGA data set. Conclusion: We observed improved treatment response with CPS in melanoma patients 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.