A Global, Randomized, Placebo-Controlled, Phase 3 Study Of Ibrutinib Plus Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, And Prednisone (Rchop) In Patients With Previously Untreated Non-Germinal Center B-Cell-Like (Gcb) Diffuse Large B-Cell Lymphoma (Dlbcl)

Introduction DLBCL is an aggressive disease that can be classified by immunohistochemistry (IHC) into GCB and non-GCB or by gene expression profiling (GEP) into GCB, activated B-cell (ABC), and unclassified subtypes. RCHOP is the standard frontline treatment (tx) for DLBCL with a 60% cure rate. Ibrutinib (ibr), an oral covalent Bruton9s tyrosine kinase inhibitor, showed activity in relapsed/refractory ABC DLBCL. This study aimed to analyze if the addition of ibr to RCHOP would improve efficacy in previously untreated patients (pts) with non-GCB DLBCL or the ABC subtype. Methods Pts with centralized IHC-confirmed non-GCB DLBCL were randomized 1:1 to standard RCHOP with either ibr (560 mg/d, po) or placebo (pbo) on a 21-day cycle for 6 or 8 cycles. Pts were stratified by revised International Prognostic Index, region (US/Western Europe vs rest of world), and number of prespecified RCHOP cycles (6 or 8). ABC DLBCL was retrospectively identified using GEP (HTG EdgeSeq cell of origin assay). Primary end point was event-free survival (EFS), defined as time from randomization to progression, relapse from complete response (CR), initiation of tx for PET-positive or biopsy-proven residual disease after ≥ 6 cycles of RCHOP, or death, in the intent-to-treat (ITT) or ABC population. Secondary end points included progression-free survival (PFS), CR rate, overall survival (OS), and safety. Results Overall, 838 pts were randomized to ibr + RCHOP (n = 419) or pbo + RCHOP (n = 419). Median age was 62 years (yrs) with 58.5% Ibr + RCHOP did not improve EFS in pts with non-GCB (by IHC) or ABC (by GEP) DLBCL: The hazard ratio (HR) for EFS was 0.934 (95% confidence interval [CI], 0.726-1.200) for the ITT and 0.949 (95% CI, 0.704-1.279) for the ABC subset. Multivariate analysis showed a significant interaction (based on SAP prespecified 1-sided α level p Efficacy outcomes favored ibr + RCHOP-treated pts Grade ≥ 3 AE rates were 89.9% and 87.1% in the ibr + RCHOP and pbo + RCHOP arms, respectively. Serious AEs (SAEs) were greater in the ibr + RCHOP vs pbo + RCHOP arm (53.1% vs 34.0%), particularly febrile neutropenia and pneumonia, as were AEs leading to RCHOP discontinuation. In pts ≥ 65 yrs, there were more SAEs (67.4% vs 40.6%) and pts who received Conclusions While the addition of ibr to RCHOP did not improve efficacy in the ITT population, there was a significant interaction between tx and age. Among pts ≥ 65 yrs, unexpected increased toxicity associated with ibr + RCHOP resulted in reduced RCHOP exposure, which may explain in part the worse clinical benefit/risk profile of pts in the ibr + RCHOP vs pbo + RCHOP arm. However, in pts Funding Source Sponsored by Janssen. Writing assistance was provided by Liqing Xiao of PAREXEL and funded by Janssen. Disclosures Younes: JJ Pharmacyclics: Research Funding; Astra Zeneca: Research Funding; Celgene: Honoraria; Bayer: Honoraria; BMS: Honoraria, Research Funding; Incyte: Honoraria; Curis: Research Funding; Novartis: Research Funding; Seattle Genetics: Honoraria; Genentech: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Takeda: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria; Merck: Honoraria. Sehn: Lundbeck: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Johnson: Takeda: Honoraria, Travel, accommodations, expenses; Incyte: Consultancy; Celgene: Honoraria; Novartis: Honoraria; Janssen: Consultancy, Research Funding; Epizyme: Consultancy, Honoraria, Research Funding; Eisai: Research Funding; Bristol-Myers Squibb: Honoraria; Kite: Consultancy; Boeringher Ingelheim: Consultancy; Zenyaku Kogyo: Other: Travel, accommodations, expenses; Genmab: Consultancy. Zinzani: Verastem: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity9s Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau; Bayer: Membership on an entity9s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; BMS: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; Bayer: Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Takeda: Membership on an entity9s Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity9s Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity9s Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity9s Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Lopez-Hernandez: Servier: Speakers Bureau; Roche: Research Funding; Takeda: Speakers Bureau. Duhrsen: Celgene: Honoraria, Research Funding; Amgen: Research Funding; Janssen: Honoraria; Roche: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Carey: Janssen Research u0026 Development: Employment. Liu: Janssen Research u0026 Development: Employment, Equity Ownership. Shreeve: Janssen Research u0026 Development: Employment, Equity Ownership. Sun: Janssen Research u0026 Development: Employment, Equity Ownership. Vermeulen: Janssen Research u0026 Development: Employment, Equity Ownership.