Longer Term Efficacy and Safety of Subcutaneous Compared with Intravenous Rituximab: Updated Results of the Phase 3 SABRINA Study

Background: A new subcutaneous formulation of rituximab (R^SC) has been developed which offers reduced treatment burden for patients compared to intravenous rituximab (R^IV) as well as resource savings at the treatment facility. Additionally, availability of R^SC would potentially allow patients to be treated primarily IV-free with orally administered partner therapies. The Phase 3 SABRINA study (NCT01200758) investigated induction R^IV or R^SC plus chemotherapy followed by maintenance R^IV or R^SC in patients with follicular lymphoma (FL). Pharmacokinetic non-inferiority was previously reported for R^SC (1400mg) compared with R^IV (375mg/m²) as well as comparable efficacy and safety (Davies et al. Lancet Oncol 2014;15:343-52; Davies, et al. Haematologica 2015;100:P687). Here we present updated efficacy and safety results including overall response rates (ORR) at the end of maintenance and time to event (progression-free [PFS], overall [OS], and event-free [EFS] survival) data with a median follow-up of 37 months.

Methods: Patients with treatment-naïve CD20+ grade 1-3a FL (n=410) were randomized to receive R^IV or R^SC, stratified by FL International Prognostic Index score, chemotherapy regimen, and region. All patients received R^IV 375mg/m² in Cycle 1; for Cycles 2-8, patients received R^IV 375mg/m² or R^SC 1400mg every 3 weeks. Patients received ≤8 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or 8 cycles of CVP (cyclophosphamide, vincristine and prednisone). During maintenance, patients received R^IV or R^SC every 8 weeks for 2 years. Non-serious adverse events (AEs) were reported for 28 days following the last dose of rituximab. Serious AEs (SAEs) were recorded for 1 year post-treatment or until the start of new anti-lymphoma treatment. SAEs considered possibly related to study treatment were recorded indefinitely.

Results: Based on investigator assessments for the intent-to-treat population (R^IV n=205; R^SC n=205), ORR at the end of maintenance was comparable between treatment arms: (78.1%, 95% CI [71.3, 83.9] for R^IV vs. 77.9%, 95% CI [71.0, 83.9] for R^SC) (Table 1). Analyses of the time-to-event endpoints PFS (HR, 0.84, 95% CI [0.57, 1.23]) (Fig.1), EFS (HR, 0.91, 95% CI [0.64, 1.31), and OS (HR, 0.81, 95% CI [0.42, 1.57) showed no differences in efficacy for the SC vs. the IV formulation. In total, 407 patients received ≥1 dose of rituximab (safety population). Six R^SC patients discontinued treatment after Cycle 1 (R^IV in both arms) and were included in the R^IV safety population (R^IV n=210; R^SC n=197); 86% of patients started maintenance (R^IV n=178, 85%; R^SC n=172, 87%). Overall, there were similar incidences of patients with ≥1 AE (95% vs. 96%), grade ≥3 AEs (55% and 56%), and SAEs (34% and 37%) for R^IV vs. R^SC, respectively (Table 2). The most frequent AEs reported overall (R^IV vs. R^SC) were neutropenia (27% vs. 32%), nausea (22% vs. 31%), constipation (26% vs. 25%), cough (13% vs. 23%), and fatigue (18% vs. 20%). The most frequently reported AEs during the maintenance phase of the study were upper respiratory tract infection (7% vs. 11%) and cough (11% vs. 12%) for R^IV vs. R^SC, respectively. Overall, AEs associated with B-cell depletion, including neutropenia, febrile neutropenia, and grade ≥3 infections, were balanced between the SC and IV treatment arms. The change in route of administration led to an expected higher incidence of local cutaneous reactions in the R^SC arm (2% R^IV vs. 23% R^SC) with injection site erythema, injection site pain, and rash being most frequently reported. All reported events, except for 1 AE of injection site rash in the R^SC arm at Cycle 2, were of mild or moderate intensity (grade ≤2). Incidence of local cutaneous reactions decreased over subsequent treatment cycles. At data cut-off, 36 deaths had been reported: 20 (9.8%) in the R^IV arm and 16 (7.8%) in the R^SC arm.

Conclusions: Overall, there were no new clinically relevant safety signals observed with R^SC and the safety profile was comparable to that of R^IV. Response rates as well as PFS and OS data for rituximab SC were comparable to rituximab IV and indicate that the anti-lymphoma activity of rituximab is not impaired when given subcutaneously. The availability of R^SC administration over approximately 6 minutes has positive implications for patient and healthcare professional convenience, as well as healthcare resource savings, without compromising efficacy or safety.

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