Genomic Features of Exceptional Response in Vemurafenib ± Cobimetinib-treated Patients with BRAF V600-mutated Metastatic Melanoma.

Abstract

PURPOSE:

Previous investigations identified transcriptional signatures associated with innate resistance to anti-programmed cell death protein 1 therapy in melanoma. This analysis aimed to increase understanding of the role of baseline genetic features in the variability of response to BRAF and MEK inhibitor therapy for BRAF V600-mutated metastatic melanoma.

PATIENTS AND METHODS:

This exploratory analysis compared genomic features, using whole-exome and RNA sequencing, of baseline tumors from patients who had complete response versus rapid progression (disease progression at first postbaseline assessment) on treatment with cobimetinib combined with vemurafenib or vemurafenib alone. Associations of gene expression with progression-free survival or overall survival were assessed by Cox proportional hazards modeling.

RESULTS:

Whole-exome sequencing showed that MITF and TP53 alterations were more frequent in tumors from patients with rapid progression, while NF1 alterations were more frequent in tumors from patients with complete response. However, the low frequency of alterations in any one gene precluded their characterization as drivers of response/resistance. Analysis of RNA profiles showed that expression of immune response-related genes was enriched in tumors from patients with complete response, while expression of keratinization-related genes was enriched in tumors from patients who experienced rapid progression.

CONCLUSIONS:

These findings suggest that enriched immune infiltration might be a shared feature favoring response to both targeted and immune therapies, while features of innate resistance to targeted and immune therapies were distinct.

• Authors: Yibing Yan, Matthew J Wongchenko, Caroline Robert, James Larkin, Paolo A Ascierto, Brigitte Dréno, Michele Maio, Claus Garbe, Paul B Chapman, Jeffrey A Sosman, Zhen Shi, Hartmut Koeppen, Jessie J Hsu, Ilsung Chang, Ivor Caro, Isabelle Rooney, Grant A McArthur, Antoni Ribas
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 11 Pg. 3239-3246 (06 01 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 30824584 (Publication Type: Journal Article, Multicenter Study)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Azetidines
• Biomarkers, Tumor
• Piperidines
• Vemurafenib
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• cobimetinib

Topics

• Alleles
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Azetidines (administration & dosage)
• Biomarkers, Tumor
• Clinical Trials, Phase II as Topic
• Clinical Trials, Phase III as Topic
• Gene Expression Profiling
• Genomics (methods)
• Humans
• Melanoma (drug therapy, genetics, mortality, pathology)
• Mutation
• Piperidines (administration & dosage)
• Proto-Oncogene Proteins B-raf (genetics)
• Randomized Controlled Trials as Topic
• Retrospective Studies
• Treatment Outcome
• Vemurafenib (administration & dosage)
• Exome Sequencing