The evidence supporting the administration of rituximab via the subcutaneous route is based on multiple pharmacokinetics studies. Thus far there have been three phase III clinical trials providing head-to-head comparison of efficacy; two of these trials have released efficacy data.
Rituximab has been in clinical use for the treatment of patients with B-cell malignancies for close to 20 years. Its use, via intravenous administration, is currently standard of care for various B-cell non-Hodgkin lymphomas (NHLs), as well as chronic lymphocytic leukaemia (CLL).
The rituximab SC development program, relies on the premise that serum rituximab levels at least as high as those achieved after IV infusion would result in at least the same degree of target-site saturation and, as a result, provide the same degree of efficacy, regardless of the administration route.
Pharmacokinetic analyses of "trough" (trough concentrations) and AUC (area under the curve) were performed in the following clinical trials:
1. SparkThera study: follicular lymphoma, maintenance phase.r Those patients who responded to rituximab induction were recruited to a dose-finding phase, and subsequently a fixed-dose phase of the study. 124 patients were in the dose-finding phase with PK data on subcutaneous administration of 375 mg/m2, 625 mg/m2 or 800 mg/m2. A fixed subcutaneous dose of 1,400 mg was predicted to achieve non-inferiority of "trough". Phase Ib of the study recruited an additional 154 patients who were randomly assigned to receive either IV 375 mg/ m2, or subcutaneously 1,400 mg fixed dose, given at every 2 or 3-month intervals. The study confirmed that non-inferior "trough" levels were achieved by the fixed 1400 mg subcutaneous dose relative to IV rituximab 375 mg/m2 dosing during maintenance, with a comparable safety profile.
2. SABRINA stage I: follicular lymphoma, previously untreated patients.r Between 2010 and 2011,124 patients in a multinational study were randomised to receive either rituximab IV 375 mg/m2 or SC 1,400 mg fixed dose, stratified by induction chemotherapy regimen CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CVP (cyclophosphamide, vincristine, prednisone), The primary endpoint was the ratio of observed rituximab serum trough concentrations ("trough") between groups at cycle 7 (before cycle 8 dosing) of induction treatment in a per-protocol population. Safety profiles between the two groups were also compared. The authors were able to demonstrate that the geometric mean "trough" was 83.13 μg/mL in the intravenous group and 134.58 μg/mL in the subcutaneous group (ratio 1.62, 90% CI 1.36–1.94), showing non-inferiority of subcutaneous rituximab. In terms of safety, the two arms were comparable: 57 (88%) of 65 patients in the IV rituximab safety population had adverse events (30 [46%] grade ≥3), as did 57 (92%) of 62 patients in the subcutaneous rituximab safety population (29 [47%] grade ≥3).
3. SAWYER stage I: chronic lymphocytic leukaemia, previously untreated patients, dose-finding phase.r Fifty-five patients were recruited into this phase I dose-finding study, whereby standard FCR using IV rituximab 375 mg/m2 in cycle 1, 500 mg/m2 in cycles 2-5 were administered. Rituximab IV was replaced by a single fixed SC dose at cycle 6. 16 patients received 1400 mg, 17 patient received 1600 mg, and 22 patients received 1870 mg. Patients served as their own controls (i.e. pharmacokinetic values in cycle 5 [IV] were compared with those in cycle 6 [SC]). Based on "trough" measurements the authors predicted a fixed subcutaneous dose of 1600 mg would be non-inferior to the IV dose of 500 mg/m2. This dose was subsequently used in SAWYER stage II study. No major safety signals were noted.
The pharmacokinetic non-inferiority data has been summarised in a review article by Davies A et al 2017.r
© Adv Ther 2017
Direct head-to-head comparisons of the efficacy of rituximab administered via IV versus subcutaneous routes, in conjunction with chemotherapy, were conducted in the following clinical studies:
1. SABRINA part II:r Between Feb 15, 2011, and May 15, 2013, 410 patients with previously untreated follicular lymphoma were randomly assigned, 205 to IV rituximab and 205 to SC rituximab. Investigator-assessed overall response at the end of induction was 84·9% (95% CI 79·2–89·5) in the IV group and 84·4% (78·7–89·1) in the SC group. At a median follow-up of 37 months, progression-free survival (HR 0.84, 95% CI 0.57–1.23), event-free survival (0.91, 0.64–1.31), and overall survival (0.81, 0.42–1.57) did not differ significantly between the two groups.
2. MabEase:r Between August 2012 and September 2016, 576 patients with diffuse large B lymphoma were randomised 2:1 to receive either subcutaneous rituximab or intravenous rituximab, in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy in either 14 or 21 day cycles. Efficacy endpoints were tabulated in the publication by Lugtenburg et al., with no difference between the two arms at the end of induction therapy.
© Haematologica 2017
At 24 months of follow up, PFS (95% CI) was 75.0% (69.9%–79.4%) in the SC group and 81.5% (74.7% – 86.6%) in the IV group (P=0.175), and EFS (95% CI) was 68.6% (63.3%–73.4%) and 73.4% (66.0%–79.4%), respectively (P=0.456).
© Haematologica 2017
No efficacy data has been released yet on the SAWYER study for CLL as of Dec 2017, awaiting maturation of the follow-up data.r
Quality of Life considerations
The PrefMab evaluated patient preference for the SC or IV formulation of rituximab when given with chemotherapy in previously untreated patients with CD20-pos DLBCL or follicular lymphoma.r 743 patients were enrolled, with each patient having exposure to both IV and SC administration routes in varying order, in combination with standard-of-care chemotherapy for their treatment centres. The Patient Preference Questionnaire (PPQ) yielded consistent preference for SC route after cycles 6 and 8:
© Annal of Onc 2017
MabEase (DLBL) trialr used the Cancer Therapy Satisfaction Questionnaire (CTSQ) and Rituximab Administration Satisfaction Questionnaire (RASQ) for assessment of patient satisfaction, with the following graphical representation of the preferences:
© Haematologica 2017
Overall rituximab SC has been shown to be well-tolerated, with the exception of local cutaneous reactions. These were of mild-to-moderate severity, reflecting the expected safety profile of subcutaneously administered drugs.
In the SABRINA study, where rituximab was administered in combination with chemotherapy, 96% (rituximab SC) and 95% (rituximab IV) of patients experienced an adverse event, respectively. Grade >3 adverse event occurred in a similar proportion of patients (SC :56%; IV: 55%).r
© Lancet 2017
The most common any-grade adverse events were (SC vs. IV) neutropenia (32% vs. 27%), nausea (31% vs. 22%), constipation (25% vs. 26%), cough (23% vs. 13%), fatigue (20% vs. 18%), diarrhoea (18% vs. 16%), asthenia (17% vs. 13%), paraesthesia (16% vs.12%), pyrexia (15% vs. 16%), anaemia (15% vs.13%), and upper respiratory tract infection (15% vs. 10%).
In the MabEase study (patients with DLBL),r similar grade 3/4 adverse event rates (58% SC vs. 54% IV) were reported. Grade 3/4 febrile neutropenia was more frequent in the SC arm (12.5% vs. 6.9%, p = 0.0575). Injection-site reactions were reported by 5.7% of patients in the SC arm compared with no patients in the IV arm.
In the SAWYER study with CLL patients, a similar pattern of distribution of adverse events was observed when rituximab SC 1600 mg was used as comparator against standard IV doses, in combination with fludarabine and cyclophosphamide.r Proportions of patients reporting adverse events of any grade were 96% for SC and 91% for IV in this trial. The most common grade 3/4 adverse event was neutropenia (56% SC and 52% IV); the most common serious adverse event was febrile neutropenia (11% SC and 4% IV). Administration-related reactions were reported in 44% of SC and 45% of IV patients. More patients reported local cutaneous reactions after rituximab SC (42% versus 2%), with most of these reactions being grade 1/2.
One of the theoretical safety concerns has been the one-size-fits-all dosing of SC rituximab, especially in patient with low Body Surface Area (BSA), in whom antibody exposure may be greater relative to the exposure after rituximab IV BSA-adjusted dosing. Reassuringly, adverse event rates were similar for rituximab IV and SC administration in patients with low, medium, and high BSA in the SparkThera (follicular lymphoma maintenance) and SABRINA (follicular lymphoma induction combined with chemo) trials.rr These studies suggested that fixed-dose administration does not increase toxicity in low BSA patients.
In the MabEase trial (DLBL induction combined with chemo), an Exploratory Safety Analysis was incorporated, which showed an apparent higher incidence of grade 3/4 AEs and serious AEs (SAEs) in patients with low BSA (≤1.7 m2) in the SC versus the IV arm. The authors noted this observation may be driven primarily by the low number of male patients in the low BSA arm, particularly in the IV subgroup. Further statistical analyses revealed no significant interaction effect (p>0.05 for all comparisons) for AEs of grade ≥3 or SAEs with any of the covariates BSA, age group, or gender.r