Abstract CT072: Efficacy and safety of entinostat (ENT) and pembrolizumab (PEMBRO) in patients with melanoma previously treated with anti-PD1 therapy
Authors: Sullivan Ryan J. , Moschos Stergios J. , Johnson Melissa L. , Opyrchal Mateusz , Ordentlich Peter , Brouwer Susan , Sankoh Serap , Meyers Michael L. , Agarwala Sanjiv S. 
Published: August 2019

Background: Inhibitors of programmed death 1 (PD-1) and its ligand (PD-L1) have improved outcomes in patients (pts) with advanced melanoma, but treatment options for pts who progress on or after these therapies remain limited. In this group, we previously reported preliminary data that ENT, a class I selective histone deacetylase (HDAC) inhibitor, in combination with PEMBRO showed promising activity, through alteration of the immunosuppressive tumor microenvironment. Here we report the full cohort of patients enrolled.

Methods: ENCORE-601 is an open-label study evaluating ENT (5 mg PO weekly) + PEMBRO (200 mg IV Q3W) in pts with unresectable or metastatic melanoma who were previously treated with a PD-1-blocking antibody and experienced progression on or after therapy. A Simon 2-stage design was utilized (Stage 1: 13 patients, Stage 2: 40 patients) and the primary endpoint was ORR as assessed by irRECIST. Tumor biopsies and blood samples for immune correlates were obtained pre- and on-treatment.

Results: 53 patients were enrolled (the last patient entered April 2018, data cutoff is January 2018). The median duration of prior PD-1 therapy was 4.9 months and median time from last dose to study entry was 2.7 months (66% of patients had no intervening therapy between their prior PD-1 therapy and study enrollment). Additional baseline demographics are as follows: 55% were ECOG 0, 36% had elevated LDH, 70% pts had prior ipilimumab, and 23% had prior BRAF/MEK inhibitors. The confirmed objective response with ENT + PEMBRO is 19% (1 CR and 9 PRs; 95% CI: 9-32%); these results exceed the threshold for success based on the prespecified design. The median duration of response as of the cut-off date is 12.5 months (range 4-18 months) with 5 responders ongoing at the time of data cutoff. An additional 7 patients have had stable disease for &gt; 6 months, resulting in a clinical benefit rate (CR, PR, SD &gt; 6 months) of 32% (95% CI: 20%-46%). The median PFS is 4.2 months. Efficacy results in patients who received prior ipilimumab were consistent with the overall population. Among the responders, best response on prior PD-1 therapy were as follows: progression- 3 pts, stable disease- 5 pts, partial response- 1 pt, unknown- 1 pt. Grade 3/4 related AEs occurring in &gt;5% of patients included neutropenia, fatigue, and hyponatraemia. 5 patients (9%) experienced a Grade 3/4 immune-related AE (2 events of rash, 1 each of colitis, pneumonitis, and autoimmune hepatitis). Additional correlative analyses to identify biomarkers of response, including whole exome sequencing and RNAseq, are in progress.

Conclusions: In patients with melanoma who have progressed following treatment with prior PD-1 blockade, and both prior PD-1 and CTLA-4 blockade, ENT plus PEMBRO demonstrates significant clinical activity and acceptable safety.

Citation Format: Ryan J. Sullivan, Stergios J. Moschos, Melissa L. Johnson, Mateusz Opyrchal, Peter Ordentlich, Susan Brouwer, Serap Sankoh, Michael L. Meyers, Sanjiv S. Agarwala. Efficacy and safety of entinostat (ENT) and pembrolizumab (PEMBRO) in patients with melanoma previously treated with anti-PD1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT072.