Phase I/Ib Study of Pembrolizumab Plus Vorinostat in Advanced/Metastatic Non-Small Cell Lung Cancer.
Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal, Humanized
/ administration & dosage
Antineoplastic Combined Chemotherapy Protocols
/ adverse effects
Biopsy
Carcinoma, Non-Small-Cell Lung
/ diagnosis
Drug Monitoring
Female
Humans
Lung Neoplasms
/ diagnosis
Male
Middle Aged
Neoplasm Metastasis
Neoplasm Staging
Prognosis
Retreatment
Treatment Outcome
Vorinostat
/ administration & dosage
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:
15 11 2019
15 11 2019
Historique:
received:
24
04
2019
revised:
20
06
2019
accepted:
06
08
2019
pubmed:
15
8
2019
medline:
12
9
2020
entrez:
15
8
2019
Statut:
ppublish
Résumé
Histone deacetylase inhibitors (HDACi) enhance tumor immunogenicity through several mechanisms and may improve response to immune checkpoint inhibitors (ICIs). In a phase I/Ib trial, we tested the oral HDACi vorinostat combined with the programmed cell death protein 1 inhibitor pembrolizumab in advanced/metastatic non-small cell lung cancer. Patients received intravenous pembrolizumab (200 mg every 3 weeks) plus oral vorinostat (200 or 400 mg/day). Primary endpoint was safety/tolerability. Secondary endpoints included response rate, progression-free survival, disease control rate (DCR), and overall survival. Tumor gene expression changes, T-cell density, and myeloid cell levels were studied in serial tissue specimens. Thirty-three patients were treated (13 in phase I, 20 in phase Ib). In phase I, both ICI-naïve and ICI-pretreated patients were enrolled to determine dose-limiting toxicities (DLT). No DLTs were observed, and the recommended phase I dose was pembrolizumab 200 mg and vorinostat 400 mg. Any-grade adverse events were mainly fatigue (33%) and nausea/vomiting (27%). Of six ICI-naïve and 24 ICI-pretreated patients evaluable for response, four (13%) had partial response [two confirmed, one unconfirmed with subsequent prolonged stable disease (SD), one unconfirmed with subsequent progressive disease (PD)], 16 (53%) had SD, and 10 (33%) had PD for a DCR of 67%. In the ICI-pretreated cohort, three patients (one confirmed, two unconfirmed) had partial response and 10 had SD. Pretreatment CD8 Pembrolizumab plus vorinostat was well tolerated and demonstrated preliminary antitumor activity despite progression on prior ICI treatment.
Identifiants
pubmed: 31409616
pii: 1078-0432.CCR-19-1305
doi: 10.1158/1078-0432.CCR-19-1305
pmc: PMC7234799
mid: NIHMS1537390
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Vorinostat
58IFB293JI
pembrolizumab
DPT0O3T46P
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6623-6632Subventions
Organisme : NCI NIH HHS
ID : P30 CA076292
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA212169
Pays : United States
Informations de copyright
©2019 American Association for Cancer Research.
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