Randomized, Double-Blind, Pharmacokinetic Equivalence Trial Comparing DRL-Rituximab With MabThera in Patients With Diffuse Large B-Cell Lymphoma.

ABSTRACT

PURPOSE: We sought to compare the pharmacokinetics (PKs) of DRL-rituximab (DRL_RI; potential biosimilar) and innovator rituximab MabThera (Roche, Grenzach-Wyhlen, Germany; reference medicinal product [RMP]) in patients with diffuse large B-cell lymphoma (DLBCL). Efficacy, pharmacodynamics (PDs), safety, and immunogenicity were also compared. PATIENTS AND METHODS: We conducted a double-blind, parallel-group study in patients with untreated DLBCL who were eligible to receive cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy. Patients were randomly assigned at a one-to-one ratio to receive DRL_RI or RMP for six 21-day cycles of rituximab plus CHOP, with 18 months of follow-up after day 1, cycle 6 (C6). Primary end point was C1 PKs, measured as area under the plasma concentration-time curve from day 0 to 21 (AUC0-21 days) and maximum plasma concentration (Cmax). Equivalence was defined as 90% CIs for the DRL_RI/RMP geometric mean ratios (GMRs) within 80% and 125%. Secondary end points included efficacy noninferiority measured by objective response rate (ORR) at C6 and event-free survival and overall survival at 87 weeks, PK equivalence at C6 and PD equivalence (rate of B-cell depletion and repletion), safety, and immunogenicity. The trial was stopped after sufficient patients for primary end point evaluation were enrolled. Secondary end points are reported as observed. RESULTS: A total of 151 patients were randomly assigned (DRL_RI, n = 76; RMP, n = 75). DRL_RI/RMP GMRs for AUC0-21 days and Cmax in C1 were 99.77 (90% CI, 87.60 to 113.63) and 96.19 (90% CI, 88.65 to 104.38), respectively. ORR at C6 for DRL_RI and RMP were 82.0% and 84.8%, respectively. Rates of B-cell depletion/repletion, immunogenicity, and adverse events were comparable in both groups. CONCLUSION: DRL_RI and RMP had equivalent PKs, with comparable efficacy, PDs, safety, and immunogenicity.