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.

Fig 1.

Response to treatment. (A) Maximum percentage change from baseline in target lesions. (B) Change from baseline in target lesions. (C) Treatment exposure and response duration. Three patients had a formal response assessment before the protocol-required time point of 12 weeks. One patient only received one dose of pembrolizumab, discontinued treatment because of toxicity at 4 weeks, and had nonprotocol scans to assess response, which showed CR. The other two patients had nonprotocol scans to confirm the clinical impression of progressive disease before the 12-week time point. Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

Fig 2.

Patient survival data. (A) Progression-free survival. (B) Overall survival.

Fig 3.

Distribution of the changes from baseline to cycle 7 (N = 9) on the natural log scale in the absolute count of CD4 and CD8 T cells, total T cells, and natural killer (NK) cells.