Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure

Abstract

Purpose Classical Hodgkin lymphoma (HL) frequently exhibits genetic alterations leading to overexpression of the programmed death-1 (PD-1) ligands, suggesting a possible vulnerability to PD-1 blockade. The phase Ib study KEYNOTE-013 (NCT01953692) tested the safety and efficacy of the anti-PD-1 antibody pembrolizumab in patients with hematologic malignancies. Based on its genetics, HL was included as an independent cohort. Methods We enrolled patients with relapsed or refractory HL whose disease progressed on or after treatment with brentuximab vedotin. Patients received pembrolizumab, 10 mg/kg every 2 weeks, until disease progression occurred. Response to treatment was assessed at week 12 and every 8 weeks thereafter. Principal end points were safety and complete remission (CR) rate. Results Thirty-one patients were enrolled; 55% had more than four lines of prior therapy, and 71% had relapsed after autologous stem cell transplantation. Five patients (16%) experienced grade 3 drug-related adverse events (AEs); there were no grade 4 AEs or deaths related to treatment. The CR rate was 16% (90% CI, 7% to 31%). In addition, 48% of patients achieved a partial remission, for an overall response rate of 65% (90% CI, 48% to 79%). Most of the responses (70%) lasted longer than 24 weeks (range, 0.14+ to 74+ weeks), with a median follow-up of 17 months. The progression-free survival rate was 69% at 24 weeks and 46% at 52 weeks. Biomarker analyses demonstrated a high prevalence of PD-L1 and PD-L2 expression, treatment-induced expansion of T cells and natural killer cells, and activation of interferon-γ, T-cell receptor, and expanded immune-related signaling pathways. Conclusions Pembrolizumab was associated with a favorable safety profile. Pembrolizumab treatment induced favorable responses in a heavily pretreated patient cohort, justifying further studies.

Pembrolizumab (Keytruda)

“…In a phase 2 study, 60 31 patients with relapsed or refractory classical Hodgkin lymphoma not responding to or relapsing from previous brentuximab vedotin therapy, and who had relapsed after or were ineligible for autologous hematopoietic stem cell transplantation (ASCT), received pembrolizumab at 10 mg/kg every 2 weeks. Response was first assessed after 12 weeks (6 courses) of treatment, and then every 8 weeks thereafter.…”

The emerging role of immune checkpoint inhibition in malignant lymphoma

“…Similarly to nivolumab, treatment was well tolerated, with grade 3 drug-related adverse events reported in five patients and no grade 4 adverse events or treatment-related deaths. 36 Preliminary results of a multicohort phase II trial in r/r HL patients were presented at EHA and ASCO 2016. The results showed promising activity: in cohort 1 (r/r HL after autologous SCT and BV), cohort 2 (ineligible for autologous SCT after BV) and cohort 3 (r/r HL after autologous SCT without BV) investigator-based ORR of 73%, 83% and 73%, respectively, were reported.…”

The immune microenvironment in Hodgkin lymphoma: T cells, B cells, and immune checkpoints

“…Expression of PD-L1 is unlikely to predict response, as it is amplified in the overwhelming majority of patients treated with checkpoint inhibitors. A recent analysis of peripheral blood from patients treated with the anti-PD-1 antibody pembrolizumab demonstrated an increase in the absolute number of CD4+, CD8+, and NK cells with parallel gene expression profiles demonstrating an increased IFNg response signature, 118 but whether these changes correlate with treatment response has not been established. Future investigations into the mechanism of response to checkpoint blockade should focus both on evaluating the extent to which known immunosuppressive features of RS cells and the CHL microenvironment affect response to checkpoint blockade, as well as identifying the effector cells responsible for mediating this response.…”