Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma

Abstract

Purpose Hodgkin Reed-Sternberg cells harbor alterations in chromosome 9p24.1, leading to overexpression of programmed death-ligand 1 (PD-L1) and PD-L2. Pembrolizumab, a programmed death 1-blocking antibody, demonstrated a high overall response rate (ORR) in patients with relapsed or refractory classic Hodgkin lymphoma (rrHL) in phase I testing. Methods KEYNOTE-087 ( ClinicalTrials.gov identifier, NCT02453594) was a single-arm phase II study of pembrolizumab in three cohorts of patients with rrHL, defined on the basis of lymphoma progression after (1) autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV); (2) salvage chemotherapy and BV, and thus, ineligible for ASCT because of chemoresistant disease; and (3) ASCT, but without BV after transplantation. Patients received pembrolizumab 200 mg once every 3 weeks. Response was assessed every 12 weeks. The primary end points were ORR by central review and safety. Results A total of 210 patients were enrolled and treated (69 in cohort 1, 81 in cohort 2, and 60 in cohort 3). At the time of analysis, patients received a median of 13 treatment cycles. Per central review, the ORR was 69.0% (95% CI, 62.3% to 75.2%), and the complete response rate was 22.4% (95% CI, 16.9% to 28.6%). By cohort, ORRs were 73.9% for cohort 1, 64.2% for cohort 2, and 70.0% for cohort 3. Thirty-one patients had a response ≥ 6 months. The safety profile was largely consistent with previous pembrolizumab studies. Conclusion Pembrolizumab was associated with high response rates and an acceptable safety profile in patients with rrHL, offering a new treatment paradigm for this disease.

Programmed cell death protein-1 (PD-1)-expression in the microenvironment of classical Hodgkin lymphoma at relapse during anti-PD-1-treatment

“…Although durable responses to anti-PD-1 treatment have been documented, the majority of patients eventually relapse. [4][5][6] To address the important, but so far unsolved issue of mechanisms of resistance to PD-1 blockade, we retrospectively assessed sequential biopsies of r/r cHL patients developing progressive disease (PD) or relapse on anti-PD-1 treatment with regard to microenvironmental changes and PD-1 as well as PD-L1 expression.…”

“…1 Constitutional and high expression of PD-L1 by HRSC indicates a role of PD-1/PD-L1 interaction in cHL. [2][3][4][5] Inhibition of PD-1/PD-L1 interaction by anti-PD1 blockade has shown impressive response rates in r/r cHL. Although durable responses to anti-PD-1 treatment have been documented, the majority of patients eventually relapse.…”

“…Although durable responses to anti-PD-1 treatment have been documented, the majority of patients eventually relapse. [4][5][6] To address the important, but so far unsolved issue of mechanisms of resistance to PD-1 blockade, we retrospectively assessed sequential biopsies of r/r cHL patients developing progressive disease (PD) or relapse on anti-PD-1 treatment with regard to microenvironmental changes and PD-1 as well as PD-L1 expression.In nine cHL patients' formalin fixed paraffin embedded biopsy specimen prior to and a second biopsy at relapse/progression under anti-PD-1-treatment were available including three patients with three available biopsies (two patients with two biopsies before and one patient with two biopsies under anti-PD-1-treatment). All patients gave their informed consent for this study which had been approved by our local ethics committee.…”

Th17 immune microenvironment in Epstein-Barr virus–negative Hodgkin lymphoma: implications for immunotherapy

“…However, T-cell function in these tumors appears inhibited, consistent with the demonstration that CHL is exquisitely sensitive to drugs that inhibit the immune checkpoint receptor anti-PD-1. [13][14][15][16] In addition, the remarkable response rate of CHL to anti-PD-1 has led to an appreciation that copy number alterations in PD-L1 and PD-L2 are a defining feature of CHL without regard to EBV association. 13,15,17 In this study, we sought to further characterize the expression of immune checkpoint molecules and the inflammatory milieu in EBV 1 …”

Guest editorial: advances in immunotherapy for hematological malignancies

“…The clinical outcomes of anti-PD-1 monoclonal antibodies on Hodgkin's lymphoma are particularly impressive [1,2]. The tumor microenvironment of lymphoid malignancies often includes a substantial number of reactive T cells and macrophages, which may have immunosuppressive functions.…”