A Phase II Trial Investigating the Combination of Pembrolizumab (PEM) and Entinostat (ENT) in Relapsed and Refractory (R/R) Hodgkin Lymphoma (HL)

Introduction

Histone deacetylase (HDAC) inhibitors have single agent activity in various types of lymphoma. They restore antigen-specific immune recognition in cancer cells and modulate programmed cell death (PD)-1 expression. Preclinical studies have shown synergy with the combination of HDAC inhibitors and anti-PD-1 antibodies in murine models of various tumors. Herein, we present safety and efficacy data from a phase II trial investigating a novel combination of the HDAC inhibitor ENT and the PD-1-blocking antibody PEM in patients with R/R HL and FL.

Methods

Patients with R/R HL received ENT 5-7 mg orally once weekly and PEM 200 mg intravenously once every three weeks. Prior use of anti-PD-1 or HDAC inhibitor was allowed if there had been clinical benefit. Tumor assessment was evaluated using the RECIL criteria. The primary objective is 12-month progression-free survival (PFS).

Results

At time of censoring on 7/31/20, 17 patients with HL have been enrolled, including 6 currently receiving therapy on study. The median number of prior therapies was 4 (2-17) including 7 (41%) refractory to most recent therapy. 11 (65%) received prior autologous stem cell transplant (ASCT), 8 (47%) received prior anti-PD1 antibody therapy, and 3 (18%) prior HDAC inhibitor therapy. Out of 16 evaluable patients, the overall response rate (ORR) was 94% and the complete response (CR) rate was 63%. Responding patients included 6 with prior anti-PD-1 antibody and 3 with prior HDAC inhibitor therapy. With a median duration of follow-up of 8.4 months, the 12-month PFS was 84% (66%-100%) and the median PFS was not reached. The median duration on treatment was 6.6 months (range 2.3-16.2 months) with discontinuations due to progression (n=2), toxicity (n=3), consolidation with transplant (n=3) or radiation (n=1), or withdrawal of consent (n=3). Out of a total of 25 patients enrolled in this study (including an additional 8 subjects with follicular lymphoma), 76% had grade 3 adverse events (AE). 60% of patients had grade 3 hematologic AEs, including neutropenia (52%) and thrombocytopenia (32%), compared to 32% non-hematologic. The most common immune-related AEs were hypothyroidism (n=3, 12%), hepatitis (n=3, 12%) and pneumonitis (n=2, 8%). Four patients who experienced serious AEs due to pericarditis (n=2), hemophagocytic lymphohistiocytosis, and bullous dermatitis were taken off study. ENT was dose-reduced in 8 patients and was temporarily held without dose-reduction in 11 patients.

Conclusions

The combination of PEM and ENT is tolerable and induces high response rates in R/R HL, some of which appear durable, including in patients who have previously progressed on anti-PD-1 blockade.