Exome Analysis Reveals Genomic Markers Associated with Better Efficacy of Nivolumab in Lung Cancer Patients.
Clin Cancer Res
; 25(3): 957-966, 2019 02 01.
Article
en En
| MEDLINE
| ID: mdl-30154227
ABSTRACT
PURPOSE:
Immune checkpoint inhibitors revolutionized the treatment of non-small cell lung cancer (NSCLC). However, only one-quarter of patients benefit from these new therapies. PD-L1 assessment and tumor mutational burden (TMB) are available tools to optimize use of checkpoint inhibitors but novel tools are needed. Exome sequencing could generate many variables but their role in identifying predictors of response is unknown. EXPERIMENTALDESIGN:
We performed somatic and constitutional exome analyses for 77 patients with NSCLC treated with nivolumab. We studied one-tumor-related characteristics aneuploidy, CNA clonality, mutational signatures, TMB, mutations in WNT, AKT, MAPK, and DNA repair pathways, and two-immunologic characteristics number of intratumoral TCR clones, HLA types, and number of neoantigens; and six clinical parameters.RESULTS:
A high TMB per Mb, a high number of neoantigens, mutational signatures 1A and 1B, mutations in DNA repair pathways, and a low number of TCR clones are associated with greater PFS. Using a LASSO method, we established an exome-based model with nine exome parameters that could discriminate patients with good or poor PFS (P < 0.0001) and overall survival (P = 0.002). This model shows better ability to predict outcomes compared with a PD-L1 clinical model with or without TMB. It was externally validated on two cohorts of patients with NSCLC treated with pembrolizumab or with nivolumab and ipilimumab as well as in urothelial tumors treated with atezolizumab.CONCLUSIONS:
Altogether, these data provide a validated biomarker that predicts the efficacy of nivolumab or pembrolizumab in patients with NSCLC. Our biomarker seems to be superior to PD-L1 labeling and TMB models.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Biomarcadores de Tumor
/
Carcinoma de Pulmón de Células no Pequeñas
/
Genómica
/
Secuenciación del Exoma
/
Nivolumab
/
Neoplasias Pulmonares
Tipo de estudio:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Aged
/
Aged80
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
Clin Cancer Res
Asunto de la revista:
NEOPLASIAS
Año:
2019
Tipo del documento:
Article
País de afiliación:
Francia