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.