Gene Expression Profiling in <i>BRAF</i>-Mutated Melanoma Reveals Patient Subgroups with Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib.

Abstract

<b>Purpose:</b> The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with <i>BRAF</i>^V600-mutated melanoma treated with vemurafenib or cobimetinib combined with vemurafenib was evaluated.<b>Experimental Design:</b> 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 (<i>P</i> < 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.<b>Results:</b> Forty-six genes were identified as significantly associated with PFS in both BRIM-2 (<i>n</i> = 63) and the vemurafenib arm of BRIM-3 (<i>n</i> = 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, <i>P</i> = 0.0001] and in the coBRIM validation set (<i>n</i> = 101; HR, 1.6; 95% CI, 1.0-2.5; <i>P</i> = 0.08). The adverse impact of the cell-cycle signature on PFS was not observed in patients treated with cobimetinib combined with vemurafenib (<i>n</i> = 99; HR, 1.1; 95% CI, 0.7-1.8; <i>P</i> = 0.66).<b>Conclusions:</b> 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. <i>Clin Cancer Res; 23(17); 5238-45. ©2017 AACR</i>.