Efficacy of Combined VEGFR1-3, PDGFα/β, and FGFR1-3 Blockade Using Nintedanib for Esophagogastric Cancer.
Adult
Aged
Antineoplastic Agents
/ administration & dosage
Biomarkers, Tumor
Computational Biology
/ methods
Esophageal Neoplasms
/ drug therapy
Female
Humans
Indoles
/ administration & dosage
Male
Middle Aged
Molecular Targeted Therapy
/ adverse effects
Protein Kinase Inhibitors
/ administration & dosage
Receptor Protein-Tyrosine Kinases
/ antagonists & inhibitors
Signal Transduction
/ drug effects
Stomach Neoplasms
/ drug therapy
Treatment Outcome
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 07 2019
01 07 2019
Historique:
received:
20
11
2018
revised:
13
02
2019
accepted:
26
03
2019
pubmed:
7
4
2019
medline:
6
8
2020
entrez:
7
4
2019
Statut:
ppublish
Résumé
VEGFR2-directed therapy is commonly used to treat metastatic esophagogastric cancer, but disease progresses in most patients within months. Therapeutic resistance is likely mediated in part by co-occurring amplifications of the genes for multiple oncogenic receptor tyrosine kinases (RTK). We therefore tested the efficacy of combined inhibition of VEGFR1-3, PDGFα/β, and FGFR1-3 using nintedanib. Patients with metastatic esophagogastric adenocarcinoma and disease progression on first-line chemotherapy were treated with nintedanib 200 mg twice daily. The primary endpoint was progression-free survival (PFS) at 6 months; secondary endpoints included tumor response and safety. Tumor biopsies were profiled by targeted capture next-generation sequencing (NGS) to identify molecular predictors of drug response. The study achieved its primary endpoint; 6 of 32 patients (19%) were progression-free at 6 months. With a median follow-up of 14.5 months among survivors, median overall survival (OS) was 14.2 months [95% confidence interval (CI), 10.8 months-NR]. Nintedanib was well tolerated; grade ≥ 3 toxicities were uncommon and included grade 3 hypertension (15%) and liver enzyme elevation (4%). Nintedanib treatment resulted in modest disease stabilization in patients with metastatic esophagogastric cancer. Alterations in cell-cycle pathway genes and increased global copy-number alteration (CNA) burden warrant further study as prognostic or predictive biomarkers.
Identifiants
pubmed: 30952642
pii: 1078-0432.CCR-18-3789
doi: 10.1158/1078-0432.CCR-18-3789
pmc: PMC6606369
mid: NIHMS1526176
doi:
Substances chimiques
Antineoplastic Agents
0
Biomarkers, Tumor
0
Indoles
0
Protein Kinase Inhibitors
0
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
nintedanib
G6HRD2P839
Types de publication
Clinical Trial, Phase II
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3811-3817Subventions
Organisme : NCI NIH HHS
ID : L30 CA162361
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Informations de copyright
©2019 American Association for Cancer Research.
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