Purpose Rituximab (R) plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy is the standard of care in previously untreated diffuse large B-cell lymphoma (DLBCL). Obinutuzumab (G) is a glycoengineered, type II, anti-CD20 monoclonal antibody. GOYA was a randomized phase III study that compared G-CHOP with R-CHOP in patients with previously untreated advanced-stage DLBCL. Methods Patients (N = 1,418) were randomly assigned to receive eight 21-day cycles of G (n = 706) or R (n = 712), plus six or eight cycles of CHOP. Primary end point was investigator-assessed progression-free survival (PFS). Results After median observation of 29 months, the number of investigator-assessed PFS events was similar between G (201; 28.5%) and R (215; 30.2%), stratified hazard ratio was 0.92 (95% CI, 0.76 to 1.11; P = .39), and 3-year PFS rates were 70% and 67%, respectively. Secondary end points of independently reviewed PFS, other time-to-event end points, and tumor response rates were similar between arms. In exploratory subgroup analyses, patients with germinal-center B cell-like subtype had a better PFS than did patients with activated B cell-like subtype, irrespective of treatment. Frequencies of grade 3 to 5 adverse events (AEs; 73.7% v 64.7%, respectively) and serious AEs (42.6% v 37.6%, respectively) were higher with G-CHOP compared with R-CHOP. Fatal AE frequencies were 5.8% for G-CHOP and 4.3% for R-CHOP. The most common AEs were neutropenia (G-CHOP, 48.3%; R-CHOP, 40.7%), infusion-related reactions (G-CHOP, 36.1%; R-CHOP, 23.5%), nausea (G-CHOP, 29.4%; R-CHOP, 28.3%), and constipation (G-CHOP, 23.4%; R-CHOP, 24.5%). Conclusion G-CHOP did not improve PFS compared with R-CHOP in patients with previously untreated DLBCL. AEs reported with G were consistent with the known safety profile. Biomarker analyses may help define a future role for G in DLBCL.

The fixed dose of 1,400 mg SC rituximab predicted by using stage 1 results was confirmed to have noninferior Ctrough levels relative to IV rituximab 375 mg/m2 dosing during maintenance, with a comparable safety profile. Additional investigation will be required to determine whether the SC route of administration for rituximab provides equivalent efficacy compared with that of IV administration.

Emicizumab, a bispecific monoclonal antibody, bridges activated factor IX (FIXa) and FX, replacing the function of missing FVIIIa to restore effective hemostasis in persons with hemophilia A (PwHA). Here we assess pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers in PwHA with FVIII inhibitors in the Phase III HAVEN 1 study (NCT02622321). Blood samples from 112 PwHA receiving 1.5 mg/kg once-weekly subcutaneous emicizumab were analyzed at central laboratories. Emicizumab concentrations for PK analysis were measured via validated immunoassay. PD effects were assessed using FVIII chromogenic activity assay containing human factors (Hyphen Biophen FVIII:C), and by FXIa-triggered thrombin generation (TG). Activated partial thromboplastin time (aPTT), prothrombin time (PT), antigen levels of FIX and FX, fibrinogen, D-dimer, and prothrombin fragment 1.2 (PF1.2) levels were determined. Emicizumab trough concentrations ≥ 50 µg/mL were maintained throughout the study. FVIII-like activity and TG (peak height) correlated with emicizumab concentrations and remained above 20 U/dL and 100 nM, respectively, with a weekly maintenance dose, theoretically converting persons with severe hemophilia A to a mild disease phenotype. aPTT was normalized at subtherapeutic concentrations of emicizumab. Plasma concentrations of target antigens FIX and FX were not significantly affected by emicizumab treatment; nor were fibrinogen, PT (international normalized ratio), D-dimer, or PF1.2. The PK profile of once-weekly emicizumab in HAVEN 1 provides sustained therapeutic plasma levels, consistent with population PK models. Both the PK profile and the PD and safety biomarkers are consistent with the established efficacy of emicizumab prophylaxis in PwHA with FVIII inhibitors.

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