Phase II randomized trial of first-line pembrolizumab and vorinostat in patients with metastatic NSCLC (mNSCLC): Final results.

9125 Background: Histone deacetylase inhibitors enhance tumor immunogenicity through various mechanisms including induced expression of MHC and T cell chemokines. A previous phase I trial demonstrated the combination of pembrolizumab (P) with vorinostat (V) in advanced/metastatic (m)NSCLC was well tolerated with signals of activity in ICI-pretreated pts. To further investigate the combination, we conducted a first-line, phase II trial. Methods: Pts with treatment-naïve mNSCLC and tumor PD-L1 expression ≥ 1% were eligible. Pts were randomized, open-label, 1:1 to receive P 200 mg IV q3 wk as monotherapy [Arm A] vs P 200 mg IV q3 wk plus V 400 mg PO daily [Arm B]. The primary endpoint was overall response rate (ORR). Secondary endpoints included DOR, PFS and OS. Tumor biopsies were collected both pre- and on-treatment (day 15-21) for exploratory correlative analysis including gene expression and changes in the tumor microenvironment. Results: Between 7/2017 – 2/2022, 86 pts were enrolled, with 83 pts evaluable for response (40 in Arm A and 43 in Arm B). Median age was 69 (range 44 - 87), 47% female, and ECOG PS 0/1 in 9%/91%. PD-L1 TPS was ≥50% in 20/40 (50%) of pts in Arm A, and in 23/46 (50%) of pts in Arm B. The most common TRAEs in Arm A included diarrhea (15%) and fatigue (10%). 3 pts in Arm A experienced grade ≥ 3 irAEs (including 1 each of grade 3 hepatitis, pneumonitis, and rash). The most common TRAEs in Arm B included fatigue (41%), nausea (44%), diarrhea (35%) and increased creatinine (33%). 3 pts in Arm B experienced grade ≥ 3 irAE (2 grade 3 pneumonitis and 1 grade 4 myopericarditis). In Arm B, 22/45 (49%) of pts had a dose-reduction in vorinostat, most commonly due to grade 2-3 fatigue or nausea. Efficacy results by intention-to-treat are summarized in the Table below. For evaluable patients only, ORR was 44% in Arm B (19/43) and 28% in Arm A (11/40) (p=0.18). RNA-sequencing of a subset of patients showed a significant increase in interferon-γ pathway activity in both Arms. However, between the two Arms, interferon-γ pathway activity was enhanced to greater extent in Arm B, which may have contributed the higher overall response rate. Conclusions: To our knowledge, this is the first randomized trial investigating the combination of HDAC inhibition and anti-PD1 therapy in NSCLC. Although the combination arm had a numerically higher ORR compared to P monotherapy, the result did not meet the primary endpoint for significance. While there were no new safety signals with the combination therapy, reduction or interruption in V dose occurred frequently, which may have contributed to lack of survival differences between arms. Clinical trial information: NCT02638090 . [Table: see text]