Phase 1 trial of Vismodegib and Erlotinib combination in metastatic pancreatic cancer.
EGFR
Erlotinib
GLI1
Hedgehog
Pancreatic cancer
Vismodegib
Journal
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]
ISSN: 1424-3911
Titre abrégé: Pancreatology
Pays: Switzerland
ID NLM: 100966936
Informations de publication
Date de publication:
Jan 2020
Jan 2020
Historique:
received:
17
09
2019
revised:
16
11
2019
accepted:
20
11
2019
pubmed:
4
12
2019
medline:
26
11
2020
entrez:
3
12
2019
Statut:
ppublish
Résumé
Interplay between the Hedgehog (HH) and epidermal growth factor receptor (EGFR) pathways modulating the outcome of their signaling activity have been reported in various cancers including pancreatic ductal adenocarcinoma (PDAC). Therefore, simultaneous targeting of these pathways may be clinically beneficial. This Phase I study combined HH and EGFR inhibition in metastatic PDAC patients. Combined effects of HH and EGFR inhibition using Vismodegib and Erlotinib with or without gemcitabine in metastatic solid tumors were assessed by CT. Another cohort of patients with metastatic PDAC was evaluated by FDG-PET and tumor biopsies-derived biomarkers. Treatment was well tolerated with the maximum tolerated dose cohort experiencing no grade 4 toxicities though 25% experienced grade 3 adverse effects. Recommended phase II dose of Vismodegib and Erlotinib were each 150 mg daily. No tumor responses were observed although 16 patients achieved stable disease for 2-7 cycles. Paired biopsy analysis before and after first cycle of therapy in PDAC patients showed reduced GLI1 mRNA, phospho-GLI1 and associated HH target genes in all cases. However, only half of the cases showed reduced levels of desmoplasia or changes in fibroblast markers. Most patients had decreased phospho-EGFR levels. Vismodegib and Erlotinib combination was well-tolerated although overall outcome in patients with metastatic PDAC was not significantly impacted by combination treatment. Biomarker analysis suggests direct targets inhibition without significantly affecting the stromal compartment. These findings conflict with pre-clinical mouse models, and thus warrant further investigation into how upstream inhibition of these pathways is circumvented in PDAC.
Sections du résumé
BACKGROUND/OBJECTIVES
OBJECTIVE
Interplay between the Hedgehog (HH) and epidermal growth factor receptor (EGFR) pathways modulating the outcome of their signaling activity have been reported in various cancers including pancreatic ductal adenocarcinoma (PDAC). Therefore, simultaneous targeting of these pathways may be clinically beneficial. This Phase I study combined HH and EGFR inhibition in metastatic PDAC patients.
METHODS
METHODS
Combined effects of HH and EGFR inhibition using Vismodegib and Erlotinib with or without gemcitabine in metastatic solid tumors were assessed by CT. Another cohort of patients with metastatic PDAC was evaluated by FDG-PET and tumor biopsies-derived biomarkers.
RESULTS
RESULTS
Treatment was well tolerated with the maximum tolerated dose cohort experiencing no grade 4 toxicities though 25% experienced grade 3 adverse effects. Recommended phase II dose of Vismodegib and Erlotinib were each 150 mg daily. No tumor responses were observed although 16 patients achieved stable disease for 2-7 cycles. Paired biopsy analysis before and after first cycle of therapy in PDAC patients showed reduced GLI1 mRNA, phospho-GLI1 and associated HH target genes in all cases. However, only half of the cases showed reduced levels of desmoplasia or changes in fibroblast markers. Most patients had decreased phospho-EGFR levels.
CONCLUSIONS
CONCLUSIONS
Vismodegib and Erlotinib combination was well-tolerated although overall outcome in patients with metastatic PDAC was not significantly impacted by combination treatment. Biomarker analysis suggests direct targets inhibition without significantly affecting the stromal compartment. These findings conflict with pre-clinical mouse models, and thus warrant further investigation into how upstream inhibition of these pathways is circumvented in PDAC.
Identifiants
pubmed: 31787526
pii: S1424-3903(19)30792-6
doi: 10.1016/j.pan.2019.11.011
pmc: PMC7195700
mid: NIHMS1580306
pii:
doi:
Substances chimiques
Anilides
0
Antineoplastic Agents
0
Biomarkers
0
HhAntag691
0
Pyridines
0
Erlotinib Hydrochloride
DA87705X9K
Types de publication
Clinical Trial, Phase I
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
101-109Subventions
Organisme : NCI NIH HHS
ID : R01 CA136526
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA102701
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA015083
Pays : United States
Organisme : NCI NIH HHS
ID : N01 CA015083
Pays : United States
Organisme : NCI NIH HHS
ID : P20 CA102701
Pays : United States
Organisme : NCI NIH HHS
ID : UM1 CA186686
Pays : United States
Informations de copyright
Copyright © 2019. Published by Elsevier B.V.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declared no conflicts with this submission.
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