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Subcutaneous Rituximab Results Published as FDA Decision Nears

Jason Harris
Published: Sunday, May 14, 2017

Dr. Andrew Davies

Andrew Davies, BSc, BM, PhD

Results from the phase III SABRINA trial showed that subcutaneous administration of rituximab (Rituxan) produced nearly identical response rates and toxicity as IV administration in the first-line treatment of follicular lymphoma. The results were published online in The Lancet Haematology.

In March, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted unanimously to recommend approval of subcutaneous rituximab for patients with treatment-naïve follicular lymphoma, treatment-naïve diffuse large B-cell lymphoma, relapsed or refractory low grade or follicular lymphoma, and treatment-naïve and relapsed or refractory chronic lymphocytic leukemia.

ODAC based its recommendation on a review of data from 5 clinical trials, which included the SABRINA study. The FDA is scheduled to issue a final decision by the end of June.

The Overall response rate (ORR) was 84.9% (95% CI, 79.2–89.5) in the IV group and 84.4% (95% CI, 78.7-89.1) in the subcutaneous group. At the end of the induction phase, patients in the IV group were slightly more likely to have complete response (CR; 84.9% vs 84.4%). Point estimates were identical for CR in both groups (32.2%; 95% CI, 25.9-39.1), and nearly identical for partial response at 52.7% (95% CI, 45.6-59.7) in the IV group versus 52.2% (95% CI, 45.1-59.2) in the subcutaneous group.

“Our findings from the 2-stage SABRINA trial show that subcutaneous rituximab is pharmacokinetically noninferior, and has similar efficacy and a similar safety profile to intravenous rituximab in first-line treatment of follicular lymphoma,” wrote the researchers, led by Andrew Davies, BSc, BM, MRCP, PhD, University of Southampton, United Kingdom. 

“Both the subcutaneous and intravenous formulations deliver identical rituximab, and the similar overall responses, complete responses, and safety profiles in the 2 study groups are consistent with the demonstrated Ctrough noninferiority of subcutaneous rituximab relative to intravenous rituximab.”

ORR at the end of maintenance was also similar in both groups, at 78.1% in the IV group and 77.9% in the subcutaneous group. In the IV group, 56.2% (95% CI, 48.6-63.6) had a CR compared with 50.6% (95% CI, 42.9-58.3) in the subcutaneous group. At a median follow-up of 37 months, progression-free survival (HR, 0.84; 95% CI, 0.57-1.23), event-free survival (HR, 0.91; 95% CI, 0.64-1.31), and overall survival (HR, 0.81; 95% CI, 0.42-1.57) did not differ significantly between groups

From February 2011 to May 2013, researchers enrolled 410 patients into the study at 113 medical centers in 30 countries. Patients were randomly assigned to 375 mg/m² of IV rituximab (n = 205) or 1400 mg of subcutaneous rituximab (n = 205), plus six to eight 21-day cycles of CHOP or eight 21-day cycles of CVP, followed by rituximab maintenance every 8 weeks.

Eligible patients had untreated, histologically confirmed, CD20-positive grade 1, 2, or 3a follicular lymphoma; ECOG performance status of 0 to 2; and bidimensionally measurable disease.

As of February 2016, all patients had completed treatment and 195 (48%) were in follow-up for progression-free survival. Another 144 (35%) were in survival follow-up after progressive disease. Median observation time for all patients was 36.8 months.

Overall, both groups experienced adverse events (AEs) at nearly identical rates, 95% in the IV group vs 96% in the subcutaneous group. The same was true for incidence of grade 3 or higher AEs, 55% versus 56%.

The most common AE’s were gastrointestinal disorders (60% in the IV group vs 66% in the subcutaneous group) and infections and infestations (64% in the IV group vs 67% in the subcutaneous group).

Neutropenia was the most common grade 3 or higher AE, occurring in 21% of the IV group and 26% of the subcutaneous group. Seventy-two (34%) IV group patients experienced serious AEs versus 73 patients (37%) in the subcutaneous group.

Administration-related AEs, mostly grade 1 or 2 local injection-site reactions, were more common in the subcutaneous group at 48% versus 35%.

Pharmacokinetic analyses at stage 2 induction were in line with stage 1 findings. Stage 1 geometric mean Ctrough was noninferior for subcutaneous rituximab compared with IV administration. Geometric mean ratio was 1.5 (90% CI, 1.3-1.7) and the coefficient of variation was similar in both arms (43.6% for subcutaneous administration vs 42.5% for IV). Researchers also said that pharmacokinetic findings were similar in both groups during the maintenance phase of stage 2.
Davies A, Merli F, Mihaljević B, et al. Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial [published online May 2, 2017]. Lancet Hamematol. doi: 10.1016/S2352-3026(17)30078-9.



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