Pembrolizumab in combination with epigenetic therapy is safe and active in heavily treated patients with peripheral T‐cell lymphoma and cutaneous T‐cell lymphoma

Abstract

Introduction: Peripheral T-cell lymphomas are uniquely sensitive to epigenetic modifiers. We have shown that decitabine and 5-azacytidine (Marchi et al.; Br. J. Haematol. 171; 2015) induce the expression of cancer testis antigens in pre-clinical models of PTCL, and that pralatrexate modulates genes involved in cytokine production, viral response and apoptosis. These data suggest a role for the incorporation of the immune-checkpoint inhibitor, pembrolizumab, to epigenetic agents. Herein we report on the clinical activity of this approach in patients with relapsed or refractory (R/R) PTCL and CTCL. Methods: This is a phase 1b study of pembrolizumab combined with pralatrexate (Arm A), pralatrexate + decitabine (Arm B), or decitabine (Arm C) in patients with R/R PTCL and CTCL. A 3+3 dose-escalation/de-escalation is applied in Arms A and C while a DLT-adapted partial order continual reassessment method for dose-finding with combinations of agents is applied in Arm B. Changes in serum cytokine levels were assessed during cycle 1 using a Luminex-based immunoassay. T-cell subpopulation profiling in peripheral blood was performed using a multi-color flow cytometry assay (Cytek® Aurora). Results: Patient characteristics, toxicity data, and response analysis are shown in table 1. Serum levels of three cytokines, TNFα, MIP-3α and IL-10, measured at day 1 pre-treatment were significantly elevated (p = 0.0001, 0.011 and 0.0017, respectively) in trial patients compared to healthy controls. Patients who responded to treatment demonstrated a more consistent decline in levels of TNFα, MIP-3α, and IL-10 during cycle 1, whereas non-responders showed stable to increased levels of these cytokines. T-cell subpopulation analysis (n = 6) showed mean CD4:CD8 ratio of 0.5 in trial patients prior to treatment compared to 1.5 for healthy age and sex-matched controls (p = 0.016). No significant change in the proportion of PD1+CD8+ central memory cells was seen in trial patients between D0 and D28 of treatment (p = 0.12), and between D0 in comparison to healthy controls (p = 0.11). The proportion of PD1+CD8+ effector T cells was lower in trial patients relative to healthy controls both before and after treatment (p = 0.04 and 0.001, respectively). There was no difference in the proportion of PD1+CD8+ effector T cells among trial patients from D0 to D28 of treatment (p = 0.19). Patients who responded to treatment (n = 3), had a lower proportion of PD1+ CD8+ effector cells at the start of treatment relative to non-responders (p = 0.002). Conclusions: These clinical data suggest that the integration of pembrolizumab on an epigenetic backbone is safe and demonstrates encouraging responses in heavily treated patients with PTCL and CTCL. These correlative data suggest that specific cytokines (TNFα, MIP-3α, and IL-10) and changes in circulating T-cell subpopulations may have predictive value as biomarkers of disease response. The research was funded by: Merck and Co. Ongoing Trial Keywords: Aggressive T-cell non-Hodgkin lymphoma, Combination Therapies, Ongoing Trials Conflicts of interests pertinent to the abstract. N. N. Benani Consultant or advisory role: Vividion Therapeutics, Kymera, Secura Bio, Affirmed GmbH, Astellas Pharma, Acrotech Biopharma LLC M. E. Williams Consultant or advisory role: Astra Zeneca, Gilead, Janssen, Kite Pharma, Kymera, TG Therapeutics Honoraria: International Oncology Network, Research to Practice Research funding: Janssen, Kymera, Pharmacyclics J. S. Manavalan Research funding: Astex O. A. O'Connor Employment or leadership position: TG Therapeutics Stock ownership: TG Therapeutics E. Marchi Employment or leadership position: Myeloid Therapeutics Consultant or advisory role: Myeloid Therapeutics Honoraria: Kyowa Kirin Research funding: Merck and Co., Celgene/BMS, Astex, NomoCan Pharmaceuticals Other remuneration: University of Virginia (Patents & Royalties: 3062/170 PROV), Daiichi Sankyo (advisory board)