Cobimetinib + vemurafenib and vemurafenib alone have improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients with BRAFV600-mutated metastatic melanoma. However, responses to these BRAF and MEK inhibitors vary between patients. The role of baseline genetic features in variability of response has yet to be fully elucidated. We describe a comparison of genomic features of tumors from CR vs PD.
Baseline tumors from CR and PD (progression at first evaluation) from the BRIM2, BRIM3, BRIM7, and coBRIM trials were analyzed by whole exome sequencing (WES) and RNA sequencing (RNA-Seq). Differences between CR and PD were tested by ANOVA. Gene signatures represent the mean Z-score of all components. Associations of gene expression with PFS or OS were assessed by Cox proportional hazards modeling.
Melanomas from 52 CR and 78 PD were characterized by WES. Preliminary analysis showed higher rates of MITF amplification (18% vs 4%) and TP53 mutation (19% vs 5%) in PD than CR, whereas NF1 deletion and deleterious mutations were more common in CR than PD (12% vs 3%). Mutational load was similar in CR and PD. Tumors from 32 CR and 40 PD were evaluated by RNA-Seq. Initial analysis showed 415 genes differentially expressed between groups that were also associated with PFS or OS. Innate anti-PD1 resistance signatures (IPRES; Hugo et al. Cell. 2016;165:35-44) were not significantly different between PD vs CR, but gene signatures of CD8 T effector cells, cytolytic T-cells, antigen presentation and NK cells were significantly enriched in CR tumors. Interestingly, 19 keratin genes and 7 kallikrein genes were expressed at significantly higher levels in PD tumors, reminiscent of the “keratin” subtype proposed by The Cancer Genome Atlas project.
These exploratory analyses revealed genomic differences between melanomas from CR vs PD treated with cobimetinib combined with vemurafenib or vemurafenib alone. Melanomas from CR possessed higher pre-existing tumor immunity features, while melanomas from PD may be overrepresented by the “keratin” molecular subtype.
Clinical trial identification
Legal entity responsible for the study
F. Hoffmann-La Roche, Ltd.
This study was funded by F. Hoffmann-La Roche, Ltd.
Y. Yan: Employment: Genentech/Roche; Stock or Other Ownership: Genentech/Roche; Patents, Royalties, Other Intellectual Property: Genentech/Roche); Travel, Accommodations, Expenses: Genentech/Roche). C. Robert: Advisory board/honoraria: BMS, Roche, GSK, Novartis, Merck, Amgen. J. Larkin: Institutional research support from MSD, BMS, Pfizer and Novartis and nonremunerated consultancy for GSK, Novartis, MSD, BMS, Pfizer and Roche/Genentech. P.A. Ascierto: Consultant Or Advisory Role: BMS, Roche/Genentech, MSD, Ventana, Novartis, Amgen, Array; Research Funding (institution): BMS, Roche/Genentech, Ventana. B. Dreno: Consulting or Advisory Role: BMS, GSK, Roche, Novartis; Speakers' Bureau: BMS, GSK, Roche; Research Funding: BMS, GSK; Travel, Accommodations, Expenses: BMS, Roche. M. Maio: Honoraria, consultant/advisory role, speakers' bureau, travel/accommodation/expenses: BMS, Roche, GSK, MedImmune, MSD, AstraZeneca; research funding: BMS, MedImmune. C. Garbe: Honoraria, consulting or advisory role, travel/accommodations/expenses: Amgen, BMS, GSK, Merck, Novartis, Roche; research funding: BMS, GSK, Roche. P.B. Chapman: Advisory board: Roche/Genentech, GSK (Honoraria), LICR Research, Merck, Rgenix, Scancell (consulting). J.A. Sosman: Advisory board (honoraria): Genentech. M.J. Wongchenko: Employment: Genentech; Stock or Other Ownership: Roche, ARIAD Pharmaceuticals. J.J. Hsu: Employment: Genentech; Stock or Other Ownership: Genentech. I. Chang: Employment, Stock or Other Ownership, Honoraria, Consulting or Advisory Role, Speakers' Bureau, Patents, Royalties, Other Intellectual Property, Expert Testimony, Travel, Accommodations, Expenses, Other: Genentech. I. Caro, I. Rooney: Employment: Genentech/Roche; Stock or Other Ownership: Roche. G. McArthur: Consulting or Advisory Role: Provectus; Research Funding: Pfizer, Celgene, and Ventana; Travel, Accommodations, Expenses: Roche and Novartis. A. Ribas: Stock or Other Ownership: Compugen, CytomX, Five Prime, and Kite Pharma; Consulting or Advisory Role: Pfizer, Merck, Amgen, and Roche.