Introduction: Entinostat is an oral Class I selective histone deacetylase inhibitor (HDACi), shown in preclinical models to enhance the anti-tumor activity of immune checkpoint blockade through reduction in the number and function of immune suppressive cells in the tumor microenvironment. Encouraging preliminary activity of entinostat (5 mg PO weekly) in combination with pembrolizumab (200 mg IV Q3W) has been previously reported in patients with melanoma and non-small cell lung cancer. This Phase 1 study was conducted to explore the impact on immune correlatives, pharmacokinetics (PK), safety and efficacy of different dose levels and schedules of entinostat combined with pembrolizumab.

Methods: Up to 30 patients with advanced solid tumors who previously completed Study SNDX-275-0140 (cardiac safety study of entinostat versus placebo) were planned to be enrolled. Patients were randomized 1:1:1 into three arms: Arm A) 1 mg entinostat Days 1-5 QW; Arm B) 5 mg entinostat Day 1 QW; Arm C) 10 mg entinostat Day 1 Q2W. All patients received 200 mg pembrolizumab Day 1 Q3W, and treatment continued until progression or unacceptable toxicity. Biomarkers were collected pre-dose & Cycle 1 Day 15, and PK samples were collected at Cycles 1, 2 and 3.

Results: 26 patients with advanced solid tumors were enrolled to Arm A (n=8), Arm B (n=9) and Arm C (n=9). No notable differences in the safety profile were observed among the 3 arms, and the overall safety profile was consistent with prior experience of entinostat combined with pembrolizumab. The most common treatment-related adverse events (>15%) included fatigue, nausea, neutropenia, dyspepsia, and pneumonitis. All of these events were Grade 1/2 with the exception of neutropenia (19.2% Grade ≥3). Three patients (breast and uterine cancer in Arm B; endometrial in Arm C) had a partial response (PR), and four patients (including 2 PRs and 2 breast cancer patients with stable disease) remain on study treatment beyond 40 weeks. All of these breast cancer patients had experienced progression of disease on hormonal therapy. PK analysis showed dose dependent increases (Arm C > Arm B > Arm A) in exposure to entinostat (AUC(Cycle 1)) with increasing variability at higher dose. Decreased numbers of monocytic myeloid derived suppressor cells (M-MDSCs; CD14+HLA-DRlow/neg) were observed in all arms, with no significant differences among arms. Protein lysine acetylation in multiple immune populations was elevated post-therapy in Arms A and B, but not Arm C, when analyzed at baseline and Cycle 1 Day 15.

Conclusions: The combination of entinostat and pembrolizumab continues to show promising activity and acceptable safety in heavily pretreated cancer patients. Consistent with previous reports, entinostat results in reductions in circulating MDSC frequency.

Citation Format: Anthony W. Tolcher, Michael L. Meyers, Dmitry Gabrilovich, Fang Wang, Jane Trepel, Min-Jung Lee, Emmett Schmitt, Christine Quaranto, Serap Sankoh, David Tamang, Peter Ordentlich. Safety, efficacy, and immune correlates of alternative doses and schedules of entinostat combined with pembrolizumab in patients with advanced solid tumors - results from SNDX-275-0141 phase I trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT179.