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. (C) 2019 by American Society of Clinical Oncology
[1]Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA;
[2]BC Canc Agcy, Vancouver, BC, Canada;
[3]Univ Southampton, Southampton, Hants, England;
[4]Seragnoli Univ Bologna, Bologna, Italy;
[5]Fudan Univ, Shanghai, Peoples R China;
[6]Peking Univ, Canc Hosp, Beijing, Peoples R China;
[7]Azienda Osped Osped Riuniti Villa Sofia Cervello, Palermo, Italy;
[8]Charles Univ Prague, Hradec Kralove, Czech Republic;
[9]Univ Hosp Hradec Kralove, Hradec Kralove, Czech Republic;
[10]Reg Clin Hosp, Nizhnii Novgorod, Russia;
[11]Univ Ulsan, Seoul, South Korea;
[12]Helsinki Univ Hosp, Helsinki, Finland;
[13]Univ Helsinki, Helsinki, Finland;
[14]Kindai Univ, Osakasayama, Japan;
[15]Ondokuz Mayis Univ, Samsun, Turkey;
[16]Jagiellonian Univ, Krakow, Poland;
[17]Sunnybrook Odette Canc Ctr, Toronto, ON, Canada;
[18]Rabin Med Ctr, Petah Tiqwa, Israel;
[19]Tel Aviv Univ, Tel Aviv, Israel;
[20]China Med Univ Hosp, Taichung, Taiwan;
[21]Univ Hosp Vall dHebron, Barcelona, Spain;
[22]Univ Hosp Essen, Essen, Germany;
[23]Hop St Louis, Paris, France;
[24]Diderot Univ, Sorbonne Paris Cite, Paris, France;
[25]Santa Casa Med Sch, Sao Paulo, Brazil;
[26]Janssen Res & Dev, San Diego, CA USA;
[27]Janssen Res & Dev, Spring House, PA USA;
[28]Janssen Res & Dev, Raritan, NJ USA;
[29]Janssen Res & Dev, Leiden, Netherlands;
[30]NCI, NIH, Bethesda, MD 20892 USA;
[31]Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA;
[32]Univ Hosp Cologne, Cologne, Germany;
[33]Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA;
[34]Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA
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