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.

Biometric Research Branch Division of Cancer Treatment and Diagnosis National Cancer Institute National Institutes of Health Bethesda Maryland

Cancer Sciences Unit Faculty of Medicine University of Southampton Southampton United Kingdom

Celgene Corporation Boudry Switzerland

Celgene Corporation Summit New Jersey

Centre for Lymphoid Cancers BC Cancer Agency Vancouver British Columbia Canada

Department of Haematology Derriford Hospital Plymouth United Kingdom

Department of Hematology Charles University Hospital Prague Czech Republic

Department of Pathology Laboratory Medicine and Lineberger Comprehensive Cancer Center University of North Carolina Chapel Hill North Carolina

Departments of Laboratory Medicine and Pathology and Hematology Mayo Clinic Rochester Minnesota

Division of Molecular and Clinical Cancer Sciences The Christie Foundation Trust Manchester United Kingdom

Division of Oncology Washington University School of Medicine St Louis Missouri

Divison of Haematology Royal Adelaide Hospital and University of Adelaide Adelaide Australia

Hematology Department Hospices Civils de Lyon Centre Hospitalier Lyon Sud Pierre Benite France

Institute of Hematology and Medical Oncology University of Bologna Bologna Italy

Laboratoire D'Anatomie Pathologique Centre Hospitalier Universitaire Purpan Toulouse France

Lymphoid Malignancies Branch Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda Maryland

Molecular Characterization and Clinical Assay Development Laboratory Leidos Biomedical Research Inc and Frederick National Laboratory for Cancer Research Frederick Maryland

Molecular Characterization Laboratory Frederick National Laboratory for Cancer Research National Cancer Institute National Institutes of Health Frederick Maryland

Roswell Park Cancer Institute Buffalo New York

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