In:
Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 22 ( 2019-11-15), p. 6623-6632
Abstract:
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 and Methods: 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. Results: 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+ T-cell presence in tumor stromal regions was associated with treatment benefit. Conclusions: Pembrolizumab plus vorinostat was well tolerated and demonstrated preliminary antitumor activity despite progression on prior ICI treatment.
Type of Medium:
Online Resource
ISSN:
1078-0432
,
1557-3265
DOI:
10.1158/1078-0432.CCR-19-1305
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2019
detail.hit.zdb_id:
1225457-5
detail.hit.zdb_id:
2036787-9
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