title: 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.
authors.affiliation: Philippe Armand and Margaret A. Shipp, Dana-Farber Cancer Institute, Boston, MA; Vincent Ribrag and Jean-Marie Michot, Institut Gustave Roussy, Villejuif, France; Pier Luigi Zinzani, Institute of Hematology Seràgnoli, University of Bologna, Bologna, Italy; John Kuruvilla, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Ellen S. Snyder, Alejandro D. Ricart, Arun Balakumaran, and Shelonitda Rose, Merck, Kenilworth, NJ; and Craig H. Moskowitz, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Philippe
authors.initials: P
authors.lastname: Armand
authors.affiliation: Philippe Armand and Margaret A. Shipp, Dana-Farber Cancer Institute, Boston, MA; Vincent Ribrag and Jean-Marie Michot, Institut Gustave Roussy, Villejuif, France; Pier Luigi Zinzani, Institute of Hematology Seràgnoli, University of Bologna, Bologna, Italy; John Kuruvilla, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Ellen S. Snyder, Alejandro D. Ricart, Arun Balakumaran, and Shelonitda Rose, Merck, Kenilworth, NJ; and Craig H. Moskowitz, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Shipp
authors.affiliation: Philippe Armand and Margaret A. Shipp, Dana-Farber Cancer Institute, Boston, MA; Vincent Ribrag and Jean-Marie Michot, Institut Gustave Roussy, Villejuif, France; Pier Luigi Zinzani, Institute of Hematology Seràgnoli, University of Bologna, Bologna, Italy; John Kuruvilla, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Ellen S. Snyder, Alejandro D. Ricart, Arun Balakumaran, and Shelonitda Rose, Merck, Kenilworth, NJ; and Craig H. Moskowitz, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Vincent
authors.initials: V
authors.lastname: Ribrag
authors.affiliation: Philippe Armand and Margaret A. Shipp, Dana-Farber Cancer Institute, Boston, MA; Vincent Ribrag and Jean-Marie Michot, Institut Gustave Roussy, Villejuif, France; Pier Luigi Zinzani, Institute of Hematology Seràgnoli, University of Bologna, Bologna, Italy; John Kuruvilla, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Ellen S. Snyder, Alejandro D. Ricart, Arun Balakumaran, and Shelonitda Rose, Merck, Kenilworth, NJ; and Craig H. Moskowitz, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Michot
authors.affiliation: Philippe Armand and Margaret A. Shipp, Dana-Farber Cancer Institute, Boston, MA; Vincent Ribrag and Jean-Marie Michot, Institut Gustave Roussy, Villejuif, France; Pier Luigi Zinzani, Institute of Hematology Seràgnoli, University of Bologna, Bologna, Italy; John Kuruvilla, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Ellen S. Snyder, Alejandro D. Ricart, Arun Balakumaran, and Shelonitda Rose, Merck, Kenilworth, NJ; and Craig H. Moskowitz, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Zinzani
authors.affiliation: Philippe Armand and Margaret A. Shipp, Dana-Farber Cancer Institute, Boston, MA; Vincent Ribrag and Jean-Marie Michot, Institut Gustave Roussy, Villejuif, France; Pier Luigi Zinzani, Institute of Hematology Seràgnoli, University of Bologna, Bologna, Italy; John Kuruvilla, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Ellen S. Snyder, Alejandro D. Ricart, Arun Balakumaran, and Shelonitda Rose, Merck, Kenilworth, NJ; and Craig H. Moskowitz, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: John
authors.initials: J
authors.lastname: Kuruvilla
authors.affiliation: Philippe Armand and Margaret A. Shipp, Dana-Farber Cancer Institute, Boston, MA; Vincent Ribrag and Jean-Marie Michot, Institut Gustave Roussy, Villejuif, France; Pier Luigi Zinzani, Institute of Hematology Seràgnoli, University of Bologna, Bologna, Italy; John Kuruvilla, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Ellen S. Snyder, Alejandro D. Ricart, Arun Balakumaran, and Shelonitda Rose, Merck, Kenilworth, NJ; and Craig H. Moskowitz, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Snyder
authors.affiliation: Philippe Armand and Margaret A. Shipp, Dana-Farber Cancer Institute, Boston, MA; Vincent Ribrag and Jean-Marie Michot, Institut Gustave Roussy, Villejuif, France; Pier Luigi Zinzani, Institute of Hematology Seràgnoli, University of Bologna, Bologna, Italy; John Kuruvilla, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Ellen S. Snyder, Alejandro D. Ricart, Arun Balakumaran, and Shelonitda Rose, Merck, Kenilworth, NJ; and Craig H. Moskowitz, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Alejandro D
authors.initials: AD
authors.lastname: Ricart
authors.affiliation: Philippe Armand and Margaret A. Shipp, Dana-Farber Cancer Institute, Boston, MA; Vincent Ribrag and Jean-Marie Michot, Institut Gustave Roussy, Villejuif, France; Pier Luigi Zinzani, Institute of Hematology Seràgnoli, University of Bologna, Bologna, Italy; John Kuruvilla, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Ellen S. Snyder, Alejandro D. Ricart, Arun Balakumaran, and Shelonitda Rose, Merck, Kenilworth, NJ; and Craig H. Moskowitz, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Arun
authors.initials: A
authors.lastname: Balakumaran
authors.affiliation: Philippe Armand and Margaret A. Shipp, Dana-Farber Cancer Institute, Boston, MA; Vincent Ribrag and Jean-Marie Michot, Institut Gustave Roussy, Villejuif, France; Pier Luigi Zinzani, Institute of Hematology Seràgnoli, University of Bologna, Bologna, Italy; John Kuruvilla, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Ellen S. Snyder, Alejandro D. Ricart, Arun Balakumaran, and Shelonitda Rose, Merck, Kenilworth, NJ; and Craig H. Moskowitz, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Shelonitda
authors.initials: S
authors.lastname: Rose
authors.affiliation: Philippe Armand and Margaret A. Shipp, Dana-Farber Cancer Institute, Boston, MA; Vincent Ribrag and Jean-Marie Michot, Institut Gustave Roussy, Villejuif, France; Pier Luigi Zinzani, Institute of Hematology Seràgnoli, University of Bologna, Bologna, Italy; John Kuruvilla, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada; Ellen S. Snyder, Alejandro D. Ricart, Arun Balakumaran, and Shelonitda Rose, Merck, Kenilworth, NJ; and Craig H. Moskowitz, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Craig H
authors.initials: CH
authors.lastname: Moskowitz
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D000074322:Antineoplastic Agents, Immunological / Q000009:adverse effects / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000378:metabolism; D000079963:Brentuximab Vedotin; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012074:Remission Induction; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D018796:Immunoconjugates; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000079963:Brentuximab Vedotin; C582435:pembrolizumab