Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAFV600-mutated melanoma treated with vemurafenib or cobimetinib combined with vemurafenib was evaluated. <br /><br />Experimental Design: Gene expression of archival tumor samples from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS (P<0 .05) were identified by univariate Cox proportional hazards modeling, then subjected to unsupervised hierarchical clustering, principal component analysis, and recursive partitioning to develop optimized gene signatures.<br /><br />Results: <p>Forty-six genes were identified as significantly associated with PFS in both BRIM-2 (n = 63) and the vemurafenib arm of BRIM-3 (n = 160). Two distinct signatures were identified: cell cycle and immune. Among vemurafenib-treated patients, the cell cycle signature was associated with shortened PFS compared with the immune signature in the BRIM-2/BRIM-3 training set (hazard ratio [HR] 1.8, 95% confidence interval [CI], 1.3-2.6, P = 0.0001) and in the coBRIM validation set (n = 101; HR 1.6, 95% CI, 1.0-2.5, P = 0.08). The adverse impact of the cell cycle signature on PFS was not observed in patients treated with cobimetinib combined with vemurafenib (n = 99; HR 1.1, 95% CI, 0.7-1.8, P = 0.66).</p> Conclusions: In vemurafenib-treated patients, the cell cycle gene signature was associated with shorter PFS. However, in cobimetinib combined with vemurafenib-treated patients, both cell cycle and immune signature subgroups had comparable PFS. Cobimetinib combined with vemurafenib may abrogate the adverse impact of the cell cycle signature.
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