Phase II Study of the PD-1 Inhibitor Pembrolizumab for the Treatment of Relapsed or Refractory Mature T-cell Lymphoma

Abstract

Background: Programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) are frequently expressed in T-cell lymphomas. This provides a rationale for exploration of immune checkpoint inhibitors in the management of T-cell lymphomas.

Patients and methods: In this phase II single-arm multicenter trial, patients with relapsed or refractory systemic T-cell lymphoma were treated with 200 mg pembrolizumab intravenously every 21 days. The primary endpoint was progression-free survival (PFS). The secondary endpoints were response rate, overall survival, response duration, and safety. We assessed PD-L1, p-AKT expression, and peripheral blood immune cells as potential predictive biomarkers.

Results: Of 18 enrolled patients, 13 were evaluable for the primary endpoint. The trial was halted early after a preplanned interim futility analysis. The overall response rate was 33% (95% confidence interval [CI], 9%-55%); 4 patients achieved a complete response (27%; 95% CI, 5%-49%). The median PFS was 3.2 months (95% CI, 1.2-3.7 months), and the median overall survival was 10.6 months (95% CI, 3.2-100 months). The median duration of response was 2.9 months (95% CI, 0-10.1 months). Two of the 4 complete responders remain in remission > 15 months. Rash was the most common adverse event (17%; n = 3). The most common ≥ grade 3 treatment-emergent adverse events were rash and pneumonitis (11%; n = 2 each). Neither PD-L1 nor p-AKT expression were associated with outcomes. However, a higher relative frequency of CD4+ T lymphocytes pre-treatment was associated with improved PFS (hazard ratio, 0.15; 95% CI, 0.03-0.74).

Conclusion: Pembrolizumab demonstrated modest single-agent activity in relapsed or refractory T-cell lymphoma.

Keywords: Angioimmunoblastic lymphoma; Immune checkpoint blockade; Immunotherapy; PD-1 inhibitor; Peripheral T cell lymphoma.

Copyright © 2019 Elsevier Inc. All rights reserved.

Figures

Fig. 1.

CONSORT diagram indicating patient flow.

Fig. 2.. Treatment outcomes.

Kaplan-Meier curves for A) Progression-free survival and B) Overall survival. Swimmer plot in C) demonstrates response duration, where each bar represents 1 subject and the length of the bar represents length of time on study. Best percent change in tumor volume is shown in D).

Fig. 3.. Relative percentage of CD4+ T lymphocytes and outcomes.

Patients who started out with a higher relative percentage of peripheral blood CD4+ T cells had a lower risk of progression. CD4+ T cells are gated as viable, CD45+ SSClow,CD3+ CD4+. A) CD4+ T cell percent of total lymphocytes (CD45+ SSClow) are shown with progressors as open squares and non-progressors as filled squares. Patients with a complete response are shown in green, while those with stable disease or partial response are shown in black. Statistical significance was measured with a Wilcoxon rank-sum test. B) Kaplan-Meyer curves of progression-free survival are shown as a function of CD4+ T cell percent of lymphocytes with the upper tertile in black, middle tertile in red, and lower tertile in blue. Green rectangles indicate censored data points. The P-value and hazard ratio were determined by a Cox proportional hazard regression.

Fig. 4.. Dynamic changes of regulatory CD4+ T cells (Treg) during treatment.

Percentage of regulatory CD4+ T cells (Treg) was reduced by pembrolizumab treatment in most patients. Regulatory T cells were gated as viable, CD45+, CD3+, CD4+, CD25high, CD127low. The percentages of CD4+ T cells that are CD25high and CD127low are shown here, a population that is essentially absent in CD8+ T cells. All three plots are different representations of the same data. A) Filled circles indicate the Treg percentage of CD4+ T cells with data points from pretreatment (pre-T) and post-treatmentsamples1and2 (S1 and S2) of the same patient connected by lines. B) shows a heat map representation of the Treg percentage of CD4+ T cells according to the scale on the right. C) shows the fold change in Treg percentage of CD4+T cells as a fold change from the pre-treatment sample according to the scale on the right. Black areas in both B) and C) represent missing data.