Subcutaneous compared to intravenous delivery results in non-inferior responses and safety profile of rituximab in newly diagnosed patients with Follicular Lymphoma – results of the phase III SABRINA trial

On 2^nd May 2017, in the Lancet Haematology, Dr Andrew Davies from the University of Southampton and colleagues published results of the phase III SABRINA trial (NCT01200758).

This international, multicenter, open-label trial aimed to assess the pharmacokinetics, efficacy, and safety of rituximab induction administered subcutaneously (SC) compared to intravenously (IV), followed by maintenance therapy, in patients with treatment naïve FL.

Overall, 410 patients were enrolled from 113 centers from 30 countries, and were randomized 1:1 to receive either subcutaneous (1,400mg; 205 patients) or intravenous (375mg/m²; 205 patients) rituximab, followed by 6–8 21-day cycles of CHOP or 8 cycles of CVP (choice at discretion of treating center).

Key Highlights

Treatment

• Median duration of uninterrupted administration over all cycles: IV = 165.0 mins (IQR, 120.0–220.0); SC = 6.0 mins (IQR, 5.8–7.0)
• 377/407 (93%) and 367/407 (90%) pts completed the planned 6 or 8 cycles of induction chemotherapy, respectively
• Median treatment duration: IV = 27.1 months (IQR, 17.1–27.8); SC = 27.1 months (21.9–27.6)

Pharmacokinetics

• Geometric mean Serum Trough Concentration (C_trough) were non-inferior for SC vs. IV rituximab
• Geometric mean ratio = 1.5 (90% CI, 1.3–1.7); coefficient of variation: IV = 42.5%; SC = 43.6%

Efficacy

• ORR at end of induction: IV = 174 pts (84.9%); SC = 173 pts (84.4%)
• CR was achieved in 66 pts (32.2%; 95% CI, 25.9–39.1) in both IV and SC arms
• PR was achieved in 108 pts (52.7%; 95% CI, 46.6–59.7) in IV group and 107 pts (52.2%; 95% CI, 45.1–59.2) in SC group
• ORR at end of maintenance: IV = 139/178 pts (78.1%; 95% CI, 71.3–83.9); SC = 134/172 pts (77.9%; 95% CI, 71.0–83.9)
• CR or CRu at end of maintenance: IV = 100 pts (56.2%; 95% CI, 48.6–63.6); SC = 87 pts (50.6%; 95% CI, 42.9–58.3)
• At a median follow-up of 37 months, PFS (HR, 0.84; 95% CI, 0.57–1.23), EFS (HR, 0.91; 95% CI, 0.64–1.31), and OS (HR, 0.81; 95% CI, 0.42–1.57) did not differ significantly between IV and SC groups

Safety

• Proportion of pts who experienced ≥1 AEs: IV = 199/210 (95%); SC = 189/197 (96%)
• The most frequent AEs in the IV and SC groups were gastrointestinal disorders (60% vs. 66%), infections and infestations (64% vs. 67%), and general or administration site conditions (50% vs. 60%)
• Neutropenia was more common in the SC group than the IV group, and was the most common ≥Grade 3 AE in both groups
• Proportion of pts who experienced ≥Grade 3 AEs: IV = 116 (55%); SC = 111 (56%)
• Proportion of pts who experienced SAEs: IV = 72 pts (34%); SC = 73 pts (37%)
• The most common SAEs in the IV and SC groups were febrile neutropenia (5% vs. 6%), pneumonia (3% vs. 5%), pyrexia (2% vs. 3%), and neutropenia (2% vs. 3%)
• Number of pts who discontinued treatment due to AEs: IV = 10; SC = 14
• Number of pts who died: IV = 22; SC = 14; most frequently due to AEs (IV = 12; SC = 7) and disease progression (IV = 7; SC = 6)
• Administration-related reactions: IV = 73 (35%); SC = 95 (48%)
• The most common administration-related reactions: IV = chills (7%) and pruritus (6%); SC = injection-site erythema (11%), pruritus (6%), rash (5%), and injection-site pain (5%)
• Grade 3 administration-related reactions: IV = 8 reactions reported in 5 pts; SC = 8 reactions reported in 6 pts
• In the IV group, 2 pts experienced Grade 4 administration-related reactions (thrombocytopenia and dyspnea)

The authors concluded by stating that both IV and SC administration methods deliver the same amount of rituximab and result in similar ORRs, CRs, and toxicity profiles. This suggests that SC administration “does not compromise the anti-lymphoma activity of rituximab when given with chemotherapy” and presents are quicker, more accommodating, and more comfortable method of rituximab administration to patients.

Subcutaneous rituximab is approved in Europe under the name MabThera® (1,400mg) and recently it has been recommended for approval by the U.S. Food and Drug Administration’s Oncologic Drugs Advisory Committee in FL, DLBCL, and CLL, as reported by the Lymphoma Hub last month.  

Abstract

Background: Intravenous rituximab is the standard of care in B-cell non-Hodgkin lymphoma, and is administered over 1·5–6 h. A subcutaneous formulation could reduce patients' treatment burden and improve resource utilisation in health care. We aimed to show the pharmacokinetic non-inferiority of subcutaneous rituximab to intravenous rituximab in follicular lymphoma and to provide efficacy and safety data.

Methods: SABRINA is a two-stage, randomised, open-label phase 3 study at 113 centres in 30 countries. Eligible patients were aged 18 years or older and had histologically confirmed, previously untreated, CD20-positive grade 1, 2, or 3a follicular lymphoma; Eastern Co-operative Oncology Group performance statuses of 0–2; bidimensionally measurable disease (by CT or MRI); life expectancy of 6 months or more; adequate haematological function for 28 days or more; and one or more symptoms requiring treatment according to the Groupe d'Etudes des Lymphomes Folliculaires criteria. Patients were randomly assigned (1:1) by investigators or members of the research team via a dynamic randomisation algorithm to 375 mg/m2 intravenous rituximab or 1400 mg subcutaneous rituximab, plus chemotherapy (six-to-eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] or eight cycles of cyclophosphamide, vincristine, and prednisone [CVP]), every 3 weeks during induction, then rituximab maintenance every 8 weeks. Randomisation was stratified by selected chemotherapy, Follicular Lymphoma International Prognostic Index, and region. The primary endpoint for stage 2 was overall response (ie, confirmed complete response, unconfirmed complete response, and partial response) at the end of induction. Efficacy analyses were done in the intention-to-treat population. Pooled data from stages 1 and 2 are reported on the basis of the clinical cutoff date of the last patient completing the maintenance phase of the study. This trial is registered with ClinicalTrials.gov, number NCT01200758; new patients are no longer being recruited, but some patients are still being followed up.

Findings: Between Feb 15, 2011, and May 15, 2013, 410 patients were randomly assigned, 205 to intravenous rituximab and 205 to subcutaneous rituximab. Investigator-assessed overall response at the end of induction was 84·9% (95% CI 79·2–89·5) in the intravenous group and 84·4% (78·7–89·1) in the subcutaneous group. The frequency of adverse events was similar in both groups (199 [95%] of 210 in the intravenous group vs 189 [96%] of 197 in the subcutaneous group); the frequency of adverse events of grade 3 or higher was also similar (116 [55%] vs 111 [56%]). The most common grade 3 or higher adverse event was neutropenia, which occurred in 44 patients (21%) in the intravenous group and 52 (26%) in the subcutaneous group. Serious adverse events occurred in 72 patients (34%) in the intravenous group and 73 (37%) in the subcutaneous group. Administration-related reactions occurred in 73 patients (35%) in the intravenous group and 95 (48%) patients in the subcutaneous group (mainly grade 1 or 2 local injection-site reactions).

Interpretation: Intravenous and subcutaneous rituximab had similar efficacy and safety profiles, and no new safety concerns were noted. Subcutaneous administration does not compromise the anti-lymphoma activity of rituximab when given with chemotherapy.