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

Abstract

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.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.Results: 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).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. Clin Cancer Res; 23(17); 5238-45. ©2017 AACR.

• Authors: Matthew J Wongchenko, Grant A McArthur, Brigitte Dréno, James Larkin, Paolo A Ascierto, Jeffrey Sosman, Luc Andries, Mark Kockx, Stephen D Hurst, Ivor Caro, Isabelle Rooney, Priti S Hegde, Luciana Molinero, Huibin Yue, Ilsung Chang, Lukas Amler, Yibing Yan, Antoni Ribas
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 17 Pg. 5238-5245 (Sep 01 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 28536307 (Publication Type: Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Azetidines
• Indoles
• Piperidines
• Sulfonamides
• Vemurafenib
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• cobimetinib

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• Azetidines (administration & dosage, adverse effects)
• Disease-Free Survival
• Drug Resistance, Neoplasm (genetics)
• Female
• Humans
• Indoles (administration & dosage, adverse effects)
• Male
• Melanoma (drug therapy, genetics, pathology)
• Middle Aged
• Mutation
• Piperidines (administration & dosage, adverse effects)
• Proportional Hazards Models
• Proto-Oncogene Proteins B-raf (genetics)
• Sulfonamides (administration & dosage, adverse effects)
• Treatment Outcome
• Vemurafenib