PURPOSE: Ibrutinib has shown activity in non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL). This double-blind phase III study evaluated ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated non-germinal center B-cell DLBCL. PATIENTS AND METHODS: Patients were randomly assigned at a one-to-one ratio to ibrutinib (560 mg per day orally) plus R-CHOP or placebo plus R-CHOP. The primary end point was event-free survival (EFS) in the intent-to-treat (ITT) population and the activated B-cell (ABC) DLBCL subgroup. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 838 patients were randomly assigned to ibrutinib plus R-CHOP (n = 419) or placebo plus R-CHOP (n = 419). Median age was 62.0 years; 75.9% of evaluable patients had ABC subtype disease, and baseline characteristics were balanced. Ibrutinib plus R-CHOP did not improve EFS in the ITT (hazard ratio [HR], 0.934) or ABC (HR, 0.949) population. A preplanned analysis showed a significant interaction between treatment and age. In patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS (HR, 0.579), PFS (HR, 0.556), and OS (HR, 0.330) and slightly increased serious adverse events (35.7% v 28.6%), but the proportion of patients receiving at least six cycles of R-CHOP was similar between treatment arms (92.9% v 93.0%). In patients age 60 years or older, ibrutinib plus R-CHOP worsened EFS, PFS, and OS, increased serious adverse events (63.4% v 38.2%), and decreased the proportion of patients receiving at least six cycles of R-CHOP (73.7% v 88.8%). CONCLUSION: The study did not meet its primary end point in the ITT or ABC population. However, in patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS, PFS, and OS with manageable safety. In patients age 60 years or older, ibrutinib plus R-CHOP was associated with increased toxicity, leading to compromised R-CHOP administration and worse outcomes. Further investigation is warranted.

Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello Palermo Italy

BC Cancer Agency Vancouver British Columbia Canada

Charles University Hradec Králové Czech Republic

China Medical University Hospital Taichung Republic of China

Diderot University Sorbonne Paris Cité Paris France

Fudan University Shanghai People's Republic of China

Helsinki University Hospital Helsinki Finland

Hôpital Saint Louis Paris France

Jagiellonian University Krakow Poland

Janssen Research and Development Leiden the Netherlands

Janssen Research and Development Raritan NJ

Janssen Research and Development San Diego CA

Janssen Research and Development Spring House PA

Kindai University Osakasayama Japan

Memorial Sloan Kettering Cancer Center New York NY

National Cancer Institute National Institutes of Health Bethesda MD

Ondokuz Mayis University Samsun Turkey

Peking University Cancer Hospital Beijing People's Republic of China

Rabin Medical Center Petah Tikva Israel

Regional Clinical Hospital Nizhny Novgorod Russian Federation

Santa Casa Medical School São Paulo Brazil

Seràgnoli University of Bologna Bologna Italy

Sunnybrook Odette Cancer Centre Toronto Ontario Canada

Tel Aviv University Tel Aviv Israel

University Hospital Essen Essen Germany

University Hospital Hradec Králové Hradec Králové Czech Republic

University Hospital Vall d'Hebron Barcelona Spain

University of Helsinki Helsinki Finland

University of Southampton Southampton United Kingdom

University of Ulsan Seoul Republic of Korea

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ClinicalTrials.gov
NCT01855750

EudraCT
2013-000959-40