title: A Phase 2/3 Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Lenalidomide Versus Investigator's Choice in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma.
abstract: Purpose:Randomized, multicenter, open-label, phase 2/3 trial investigating lenalidomide versus investigator's choice (IC) in relapsed/refractory diffuse large B-cell lymphoma (DLBCL).Experimental Design:Patients with DLBCL who received ≥2 prior therapies were stratified by DLBCL subtype [germinal center B-cell (GCB) vs. non-GCB; determined by immunohistochemistry (IHC)] and then randomized 1:1 to lenalidomide (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin). Crossover to lenalidomide was permitted for IC-treated patients with radiologically confirmed progressive disease. The primary endpoint was overall response rate (ORR). Progression-free survival (PFS), overall survival, and subtype analysis [GCB vs. activated B-cell (ABC)] using gene expression profiling (GEP) were exploratory endpoints.Results:Stage 1: 102 DLBCL patients (by IHC: non-GCB,n= 54; GCB,n= 48) received ≥1 dose of lenalidomide or IC. Hematologic treatment-emergent adverse events with lenalidomide versus IC included neutropenia (42.6%; 36.4%), anemia (33.3%; 47.3%), thrombocytopenia (24.1%; 43.6%), and leukopenia (5.6%; 12.7%), respectively. Overall, lenalidomide-treated patients had an ORR of 27.5% versus 11.8% in IC (ORRs were similar regardless of IHC-defined DLBCL subtype). Median PFS was increased in patients receiving lenalidomide (13.6 weeks) versus IC (7.9 weeks;P= 0.041), with greater improvements in non-GCB patients (15.1 vs. 7.1 weeks, respectively;P= 0.021) compared with GCB (10.1 vs. 9.0 weeks, respectively;P= 0.550).Conclusions:The clinical benefit of lenalidomide monotherapy in DLBCL patients was more evident in the non-GCB subtype. Exploratory analyses suggest that this preferential benefit was more pronounced in the GEP-defined ABC population, demonstrating a need for additional studies of lenalidomide in DLBCL using GEP subtyping.Clin Cancer Res; 23(15); 4127-37. ©2017 AACR.
authors.affiliation: Roswell Park Cancer Institute, Buffalo, New York. mczuczman@celgene.com.
authors.forename: Myron S
authors.initials: MS
authors.lastname: Czuczman
authors.affiliation: Department of Hematology, Charles University Hospital, Prague, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Trněný
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Davies
authors.affiliation: Department of Haematology, Derriford Hospital, Plymouth, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Rule
authors.affiliation: Division of Molecular and Clinical Cancer Sciences, The Christie Foundation Trust, Manchester, United Kingdom.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Linton
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Nina
authors.initials: N
authors.lastname: Wagner-Johnston
authors.affiliation: Centre for Lymphoid Cancers, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.affiliation: Centre for Lymphoid Cancers, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Graham W
authors.initials: GW
authors.lastname: Slack
authors.affiliation: Laboratoire D'Anatomie Pathologique, Centre Hospitalier Universitaire Purpan, Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Brousset
authors.affiliation: Department of Pathology/Laboratory Medicine and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: David A
authors.initials: DA
authors.lastname: Eberhard
authors.affiliation: Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Hernandez-Ilizaliturri
authors.affiliation: Hematology Department, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre-Benite, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Salles
authors.affiliation: Departments of Laboratory Medicine and Pathology and Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Witzig
authors.affiliation: Institute of Hematology and Medical Oncology, University of Bologna, Bologna, Italy.
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Zinzani
authors.affiliation: Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: George W
authors.initials: GW
authors.lastname: Wright
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Yandan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Molecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
authors.forename: P Mickey
authors.initials: PM
authors.lastname: Williams
authors.affiliation: Molecular Characterization and Clinical Assay Development Laboratory, Leidos Biomedical Research Inc. and Frederick National Laboratory for Cancer Research, Frederick, Maryland.
authors.forename: Chih-Jian
authors.initials: CJ
authors.lastname: Lih
authors.affiliation: Celgene Corporation, Summit, New Jersey.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Russo
authors.affiliation: Celgene Corporation, Summit, New Jersey.
authors.forename: Anjan
authors.initials: A
authors.lastname: Thakurta
authors.affiliation: Celgene Corporation, Summit, New Jersey.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hagner
authors.affiliation: Celgene Corporation, Boudry, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fustier
authors.affiliation: Celgene Corporation, Summit, New Jersey.
authors.forename: Dale
authors.initials: D
authors.lastname: Song
authors.affiliation: Divison of Haematology, Royal Adelaide Hospital and University of Adelaide, Adelaide, Australia.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Lewis
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077269:Lenalidomide; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011379:Prognosis; D016016:Proportional Hazards Models; D000069283:Rituximab / Q000008:administration & dosage; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000069283:Rituximab; D013792:Thalidomide; D005047:Etoposide; D000077269:Lenalidomide; D000093542:Gemcitabine