ESMO 2016: Baseline Genetic Features Elucidated in Responding and Non-Responding Patients with BRAFV600-Mutated Melanoma

Melanomas from patients who respond best to BRAF -/+ MEK inhibition have genomic features of higher levels of immune features compared with patients having progressive disease

Analysis of the genomic features of biopsies of patients with metastatic BRAFV600-mutated melanoma revealed that tumour samples taken at baseline from patients who went on to achieve complete response (CR) from therapy showed higher expression of pre-existing tumour immunity features than patients who experienced progressive disease (PD) at the first evaluation. Findings from a genetic analysis of patient samples obtained in 4 trials of vemurafenib with and without cobimetinib in patients with metastatic melanoma were presented on 8 October at the ESMO 2016 Congress in Copenhagen, Denmark.

Dr. Antoni Ribas, Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, Los Angeles, CA, USA, explained that patient responses to the BRAF inhibitor, vemurafenib, and the MEK inhibitor cobimetinib vary from patient to patient, although sole vemurafenib and vemurafenib plus cobimetinib have demonstrated improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients with BRAFV600-mutated metastatic melanoma.

Baseline Genetic Features Elucidated in Responding and Non-Responding Patients with BRAFV600-Mutated Melanoma

Differential gene expression distinguishes complete responders from non-responders. © Yibing Yan, Antoni Ribas

Together with colleagues, Dr. Yibing Yan, Oncology Biomarker Development, Genentech, Inc., South San Francisco, USA, conducted this study to identify the baseline genetic features in responding and non-responding patients and elucidate the role they play in response to these agents.

This study compared genomic features of tumours at baseline with respect to patients achieving CR versus those showing PD in response to treatment. Tumour samples taken prior to treatment in the BRIM2, BRIM3, BRIM7, and coBRIM trials from patients showing CR or PD at the first evaluation were analysed by whole exome sequencing (WES) and RNA sequencing. The differences in gene signatures between patients having CR and PD were tested by ANOVA and represent the mean Z-score of all components. Associations of gene expression with PFS or OS were assessed by Cox proportional hazards modelling.

Genomic analysis were carried out with WES performed on baseline melanoma samples from 52 patients having CR and 78 showing PD following treatment with cobimetinib combined with vemurafenib or sole vemurafenib.

Although the overall mutational load was not significantly different in samples from both groups, samples from patients with PD showed higher rates of MITF amplification and TP53 mutation than patients with CR; the respective rates were of MITF amplification were 18% versus 4% and TP53 mutation rates were 19% versus 5% in patients with PD and CR, respectively. The profile of patients with CR more commonly included NF1 deletion and deleterious mutations at 12% versus 3% in PD.

Differential gene expression were analysed with RNA sequencing on tumours from 32 CR and 40 PD revealed differential expression of 415 genes between patient cohorts that were also associated with PFS or OS.

The authors found that gene expression profiles of melanoma with CR were over-represented with adaptive and innate immune responses, e.g. gene signatures of CD8 T effector cells, cytolytic T-cells, antigen presentation and NK cells were all significantly enriched in CR tumours. This finding calls further investigation of interaction between tumour cell signalling mediated by BRAF/MEK with cancer immune regulations.

Prior to this study, Dr. Ribas and colleagues revealed common features of melanoma with innate resistance to cancer immune therapy anti-PD1, defined as the innate anti-PD1 resistance signatures (IPRES; Hugo et al. Cell. 2016;165:35-44). In this analysis of resistance to BRAF/MEK inhibition, the authors found it interesting that higher levels of gene expression of 19 keratin and 7 kallikrein genes in tumours from patients having PD tumours and remarked that this was reminiscent of the “keratin” subtype of tumour proposed by The Cancer Genome Atlas (TCGA) project.

Celeste Lebbé who commented the study findings said that the frequency of mutations in any gene is too low to be a major driver in exceptional response. The enriched gene expression was associated with immune response processes in patients with CR and keratinization in patients with PD. She emphasized for a high need of superpooled analysis, avoiding mixing BRAF and BRAF/MEK inhibitors and separation of primary and secondary resistances.


They commented that these exploratory analyses revealed baseline genomic differences between melanoma from patients showing complete response compared to those having progressive disease after treatment with cobimetinib combined with vemurafenib or vemurafenib alone. Overall, melanomas from patients achieving CR had higher levels of pre-existing tumour immunity features, whereas melanoma samples from patients showing PD predominately display the “keratin” molecular subtype.



Genomic features of complete responders (CR) versus fast progressors (PD) in patients with BRAFV600-mutated metastatic melanoma treated with cobimetinib + vemurafenib or vemurafenib alone

Y. Yan, C. Robert, J. Larkin, P.A. Ascierto, B. Dreno, M. Maio, C. Garbe, P.B. Chapman, J.A. Sosman, M.J. Wongchenko, J.J. Hsu, I. Chang, I. Caro, I. Rooney, G. McArthur, A. Ribas 

This study was funded by F. Hoffmann-La Roche, Ltd.