P745: multi-center phase ib trial of the histone deactylase inhibitor entinostat + pembrolizumab in myelodysplastic syndrome or acute myeloid leukemia refractory to hypomethylating agents

Background: Patients (pts) with MDS after hypomethylating agent (HMA) failure have a poor prognosis and need novel therapies. Anti-PD1 therapy in myeloid malignancies has limited efficacy and resistance mechanisms are poorly understood. Myeloid-derived suppressor cells (MDSCs) may contribute to MDS progression and mediate resistance to anti-PD1 therapy. As histone deacetylase inhibitors (HDACi) decrease MDSCs, combination of HDACi and anti-PD1 antibody could have synergistic anti-tumor efficacy. Aims: To evaluate safety and efficacy of the HDACi entinostat + anti-PD1 antibody pembrolizumab in MDS or oligoblastic AML after HMA failure. Methods: This is an investigator-initiated, NCI-Cancer Therapy Evaluation Program (NCI-CTEP)-sponsored, multicenter, dose escalation and expansion phase 1b trial (NCT02936752). Adult (≥18 years) pts with MDS or oligoblastic AML (bone marrow [BM] blasts 20-30%) and HMA failure were enrolled. Two dose levels were tested (DL1: entinostat 8mg PO on days 1 and 8 of each 21-day cycle; DL2: entinostat 8mg PO on days 1, 8, and 15 of each 21-day cycle) with pembrolizumab 200mg IV on day 1 of each 21-day cycle starting with cycle 2. Entinostat monotherapy was given in cycle 1 to assess its impact on MDSCs. Toxicities were graded according to CTCAE-5. Dose-limiting toxicities (DLT) were defined as any of the following if deemed possibly related to therapy: Grade (G) 3/4 non-hematologic toxicity, ≥G3 immune-related adverse events (IrAE) or IrAEs resulting in pembrolizumab interruption or discontinuation during the first 2 cycles of combined therapy. Hematologic AEs were considered a DLT only if unrelated to MDS and lasting for >42 days. Primary endpoint was safety. Secondary endpoints were overall response rate (composite of CR, PR, and hematologic improvement (HI) per the 2006 IWG MDS response criteria) and change in MDSCs and PD1/PDL-1 in BM. Results: From 06/26/2017 to 02/03/2021, 28 pts (25 MDS, 3 AML) were enrolled. Median age was 74 years (range [R], 57-86). 5 pts had ≥3 prior lines of therapy. Median IPSS-R for MDS pts was 5.5 (R: 2-10). During dose escalation, 7 pts were enrolled in DL1 (1 pt not evaluable due to disease progression during DLT period) and 6 pts were treated on DL2. There was 1 DLT on DL1 (G5 pneumonia/bronchoalveolar hemorrhage (BAH) and 2 DLTs at DL2 (G3 pharyngeal mucositis and G3 anorexia). There were no hematologic DLTs during dose escalation. DL1 was expanded leading to enrollment of another 15 pts at DL1. Median duration of therapy was 3 cycles (R: 1-12) with disease progression as most common reason for treatment discontinuation (9 pts). 4 deaths occurred on study, 2 due to therapy-related complications (1 from pneumonia/BAH, 1 from multi-organ failure which occurred after the DLT period in DL2). Table 1 shows AEs. The most common non-hematologic ≥G3 AEs independent of treatment attribution were infection (32.1%), hypoxia/respiratory failure (10.7%) and dyspnea (10.7%). 6 pts had potential IrAEs of any grade (G3 pneumonitis in 2 pts). Serious AEs occurred in 14 pts (8 potentially attributed to treatment). There were no protocol-defined responses among 19 pts with first BM assessment after 3 months. 2 pts had mCR without HI (BM blasts decreased from 7% and 10% to 2% and 4%, respectively), 12 pts had stable and 5 pts had progressive disease. With a median follow-up of 5.9 months (R: 0.5–59.1 months), median OS was 6.9 months (95% CI: 4.8–13.6 months). Correlative studies showed an expansion of monocytes in a pt with mCR which was not present in pts with stable or progressive disease. Conclusion: In this multi-center phase 1b trial entinostat + pembrolizumab at DL1 was safe but had limited therapeutic efficacy in pts with MDS and oligoblastic AML after HMA failure. Correlative studies will be presented at the meeting.Keywords: MDS/AML, MDS