PURPOSE: Histone deacetylase inhibitors (HDACi) enhance tumor immunogenicity through several mechanisms and may improve response to immune checkpoint inhibitors (ICIs). In a phase 1/1b 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 (NSCLC). EXPERIMENTAL DESIGN: 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 1, 20 in phase 1b). In phase 1, both ICI-naive and ICI-pretreated patients were enrolled to determine dose-limiting toxicities (DLTs). No DLTs were observed, and the recommended phase 2 dose was pembrolizumab 200 mg and vorinostat 400 mg. Any-grade adverse events were mainly fatigue (33%) and nausea/vomiting (27%). Of 6 ICI-naive and 24 ICI-pretreated patients evaluable for response, 4 (13%) had partial response (2 confirmed, 1 unconfirmed with subsequent prolonged stable disease [SD], 1 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, 3 patients (1 confirmed, 2 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 anti-tumor activity despite progression on prior ICI treatment.