Background: The oral histone deacetylase inhibitor (HDACi) vorinostat (V) enhances tumor immunogenicity through several mechanisms and may augment response to PD-(L)1 blockade (IO). We report mature results from a phase I/Ib trial testing the combination of V with pembrolizumab (P) in mNSCLC. Methods: In phase I, pts with either IO-naïve or IO-pretreated mNSCLC were treated with P (200mg IV q3 wk) + V (200 or 400 mg PO daily). In phase Ib expansion, pts were required to have progressed on prior IO treatment. Primary endpoints were safety/tolerability; secondary endpoints included RR, PFS, DOR, and OS. Tissue and blood specimens from pre- and post-treatment were collected for correlative analyses to determine tumor gene expression changes, levels of myeloid-derived suppressor cells and changes in peripheral T-cell phenotype. Results: Between 3/2016 - 9/2017, Phase I: 14 pts were treated (4 at 200mg, and 10 at 400mg V dose); and Phase Ib: 20 pts were treated. Median age: 67 (range 38-82); Females: 11 (32%); ECOG 1: 32 (94%); and never/former/current smokers: 3/23/8 (9%/68%/23%). No DLTs were observed. The RP2D is P 200mg and V 400mg. Most common AE of any grade were fatigue (11%), anorexia (9%) and nausea/vomiting (8%). Most common G3 AE were myalgia, anemia and diarrhea. There were no G4/5 AEs. 3 (9%) pts had treatment discontinued due to toxicity. 30 pts are evaluable for response. PD-L1 expression was ≥ 1% in 18/30 (60%), and ≥ 50% in 11/30 (37%). 6 pts were IO-naïve and 24 IO-pretreated. 4 (13%) had PR (2 confirmed), 16 (53%) had SD, and 10 (33%) had PD for a disease control rate of 67%. In the IO-pretreated Ib cohort, 2 pts (1 confirmed; 1 pending repeat CT) had a PR and 10 had SD (8 confirmed). For IO-pretreated pts, mPFS was 3.2 months. For IO-naïve, mPFS was 7.6 months. Preliminary tumor RNA-seq studies showed increase in IFN gamma and HDACi target gene expression, including CXCL9. Conclusions: V + P was well tolerated. The combination demonstrates preliminary anti-tumor activity despite progression on prior IO treatment and gene expression changes consistent with mechanism of HDACi action. A randomized phase II portion of this study, examining P combined with V vs. placebo in immunotherapy naïve pts, is ongoing. Clinical trial information: NCT02638090