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J Clin Oncol. 2019 May 20;37(15):1285-1295. doi: 10.1200/JCO.18.02403. Epub 2019 Mar 22.

Randomized Phase III Trial of Ibrutinib and Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Non-Germinal Center B-Cell Diffuse Large B-Cell Lymphoma.

Author information

1
1 Memorial Sloan Kettering Cancer Center, New York, NY.
2
2 BC Cancer Agency, Vancouver, British Columbia, Canada.
3
3 University of Southampton, Southampton, United Kingdom.
4
4 "Seràgnoli" University of Bologna, Bologna, Italy.
5
5 Fudan University, Shanghai, People's Republic of China.
6
6 Peking University Cancer Hospital, Beijing, People's Republic of China.
7
7 Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.
8
8 Charles University, Hradec Králové, Czech Republic.
9
9 University Hospital Hradec Králové, Hradec Králové, Czech Republic.
10
10 Regional Clinical Hospital, Nizhny Novgorod, Russian Federation.
11
11 University of Ulsan, Seoul, Republic of Korea.
12
12 Helsinki University Hospital, Helsinki, Finland.
13
13 University of Helsinki, Helsinki, Finland.
14
14 Kindai University, Osakasayama, Japan.
15
15 Ondokuz Mayis University, Samsun, Turkey.
16
16 Jagiellonian University, Krakow, Poland.
17
17 Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada.
18
18 Rabin Medical Center, Petah Tikva, Israel.
19
19 Tel Aviv University, Tel Aviv, Israel.
20
20 China Medical University Hospital, Taichung, Republic of China.
21
21 University Hospital Vall d'Hebron, Barcelona, Spain.
22
22 University Hospital Essen, Essen, Germany.
23
23 Hôpital Saint-Louis, Paris, France.
24
24 Diderot University, Sorbonne Paris-Cité, Paris, France.
25
25 Santa Casa Medical School, São Paulo, Brazil.
26
26 Janssen Research and Development, San Diego, CA.
27
27 Janssen Research and Development, Spring House, PA.
28
28 Janssen Research and Development, Raritan, NJ.
29
29 Janssen Research and Development, Leiden, the Netherlands.
30
30 National Cancer Institute, National Institutes of Health, Bethesda, MD.

Abstract

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.

PMID:
30901302
DOI:
10.1200/JCO.18.02403

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