RUXIENCE Rx

Rheumatoid Arthritis (RA) 

The efficacy and safety of rituximab were evaluated in 2 randomized, double-blind, placebo-controlled studies (RA Study 1 [NCT00468546] and RA Study 2 [NCT00266227]) in adults with moderately to severely active RA who had a prior inadequate response to at least 1 TNF inhibitor, and had at least 8 swollen and 8 tender joints. 

In RA Study 1, patients were randomly assigned to receive either rituximab 2 × 1000mg + MTX or placebo + MTX for 24 weeks. Further courses of rituximab 2 × 1,000 mg + MTX were administered in an openlabel extension study at a frequency determined by clinical evaluation, but no sooner than 16 weeks after the preceding course of rituximab.

In RA Study 2, all patients received the first course of rituximab 2 × 1,000 mg + MTX. Patients who experienced ongoing disease activity were randomized to receive a second course of either rituximab 2 × 1,000 mg + MTX or placebo + MTX, the majority between Weeks 24-28.

Results from RA Study 1 showed the following American College of Rheumatology (ACR) responses for rituximab + MTX vs placebo + MTX at week 24, respectively:

• ACR20 response: 51% vs 18% (treatment difference, 33%; 95% CI, 26-41)

• ACR50 response: 27% vs 5% (treatment difference, 21%; 95% CI, 15-27)

• ACR70 response: 12% vs 1% (treatment difference, 11%; 95% CI 7-15)

• Rituximab + MTX also slowed the progression of structural damage after 1 year vs placebo + MTX, and further reduced for rituximab + MTX in the second year. 

Results from RA Study 2 showed the following ACR responses for rituximab + MTX vs placebo + MTX, respectively:

• ACR20 response: 45% vs 48% at week 24 (treatment difference, NA); 54% vs 45% at week 48 (treatment difference, 11%; 95% CI, 2-20)

• ACR50 response: 21% vs 27% at week 24 (treatment difference, NA); 29% vs 26% at week 48 (treatment difference, 4%; 95% CI, -4, 13)

• ACR70 response: 8% vs 11% (treatment difference, NA); 14% vs 13% at week 48 (treatment difference, 1%; 95% CI, -5, 8)

Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL

NHL Study 1

• The safety and efficacy of rituximab was evaluated in a multicenter, open-label, single-arm study in 166 patients with relapsed or refractory, low-grade or follicular, B-cell NHL who received 375 mg/m² of rituximab given as an intravenous infusion weekly for 4 doses.

• The median time to onset of response was 50 days. Disease-related signs and symptoms (including B symptoms) resolved in 64% (25/39) of those patients with such symptoms at study entry.

• The overall response rate (ORR) was 48%, of which 6% achieved complete response (CR). The median duration of response (DOR) was 11.2 months (range, 1.9 to 42.1+).

NHL Study 2

• The safety and efficacy of rituximab was evaluated in a multicenter, single-arm study in 37 patients with relapsed or refractory, low-grade NHL who received 375 mg/m² of rituximab weekly for 8 doses. 

• The ORR was 57%, of which 14% achieved CR. The median DOR was 13.4 months (range, 2.5 to 36.5+).

NHL Study 3

• The safety and efficacy of rituximab was evaluated in a multicenter, single-arm study in 60 patients with relapsed or refractory, low-grade or follicular, B-cell NHL who received 375 mg/m2 of rituximab weekly for 4 doses. 

• All patients had achieved an objective clinical response to rituximab administered 3.8-35.6 months (median 14.5 months) prior to retreatment with rituximab.

• The ORR was 38%, of which 10% achieved CR. The median DOR was 15.0 months (range, 3.0 to 25.1+).

Bulky Disease 

• In pooled data from NHL studies 1 and 3, there were 39 patients with bulky (single lesion >10 cm in diameter) and relapsed or refractory, low-grade NHL who received rituximab 375 mg/m2 weekly for 4 doses. 

• The ORR was 36%, of which 3% achieved CR. The median DOR was 6.9 months (range, 2.8 to 25.0+).

Previously Untreated, Low-Grade or Follicular, CD20-Positive, B-Cell NHL 

NHL Study 4

• The safety and efficacy of rituximab was evaluated in an open-label, multicenter study in 322 patients with previously untreated follicular NHL.

• Patients were randomly assigned 1:1 to receive up to eight 3-week cycles of CVP (cyclophosphamide, vincristine, prednisone) chemotherapy alone or in combination with rituximab 375mg/m2 on Day 1 of each cycle (R-CVP). The main outcome measure was progression-free survival (PFS), defined as the time from randomization to the first of progression, relapse, or death.

• The median PFS was 2.4 years for the R-CVP arm vs 1.4 years for the CVP arm (hazard ratio [HR], 0.44; 95% CI, 0.29-0.65; P <.0001). 

NHL Study 5

• The safety and efficacy of rituximab was evaluated in an open-label, multicenter study in 1018 patients with previously untreated follicular NHL who achieved a response (complete or partial response) to rituximab in combination with chemotherapy.

• Patients were randomly assigned 1:1 to receive either rituximab as single-agent maintenance therapy, 375mg/m² every 8 weeks for up to 12 doses or to observation. Rituximab was initiated at 8 weeks following completion of chemotherapy. The main outcome measure was PFS, defined as the time from randomization in the maintenance/observation phase to progression, relapse, or death.

• PFS was longer in patients who received rituximab as single agent maintenance therapy (HR, 0.54; 95% CI, 0.42-0.70). 

NHL Study 6

• The safety and efficacy of rituximab was evaluated in an open-label, multicenter study in 322 patients with previously untreated low-grade, B-cell NHL who did not progress after 6 or 8 cycles of CVP chemotherapy.

• Patients were randomly assigned 1:1 to receive either rituximab 375mg/m2 IV infusion once weekly for 4 doses every 6 months for up to 16 doses or no further therapeutic intervention. The main outcome was PFS, defined as the time from randomization to progression, relapse, or death.

• There was a reduction in the risk of progression, relapse, or death (hazard ratio estimate in the range of 0.36 to 0.49) for patients who received rituximab compared with those who received no additional treatment. 

Diffuse Large B-Cell NHL (DLBCL)

NHL Study 7

• The safety and efficacy of rituximab was evaluated in a randomized, active-controlled, open-label, multicenter study in 632 patients with previously untreated DLBCL, including primary mediastinal B-cell lymphoma.

• Patients were randomly assigned 1:1 to receive either cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or rituximab in combination with CHOP (R-CHOP). The main outcome was PFS, defined as the time from randomization to the first of progression, relapse, or death. 

• The median PFS was 3.1 years for the R-CHOP arm vs 1.6 years for the CHOP arm (HR, 0.69; 2-sided P <.05). The overall survival (OS) estimates at 2 years were 74% for the R-CHOP arm vs 63% for the CHOP arm (HR, 0.72; 2-sided P <.05).

• Responding patients underwent a second randomization to receive rituximab or no further therapy. Results showed that there were no further improvements in PFS or overall survival among responding patients who received R-CHOP and additional rituximab exposure beyond induction. 

NHL Study 8

• The safety and efficacy of rituximab was evaluated in a randomized, active-controlled, open-label, multicenter study in 399 patients with previously untreated DLBCL.

• Patients were randomly assigned 1:1 to receive either CHOP or R-CHOP. All patients received up to eight 3-week cycles of CHOP induction; patients in the R-CHOP arm received rituximab 375 mg/m² on Day 1 of each cycle. The main outcome measure was event-free survival, defined as the time from randomization to relapse, progression, change in therapy, or death from any cause.

• The median event-free survival was 2.9 years for the R-CHOP arm vs 1.1 years for the CHOP arm (HR, 0.60; 2-sided P <.05). The OS estimates at 2 years were 69% for the R-CHOP arm vs 58% for the CHOP arm (HR, 0.68; 2-sided P <.05). The OS estimates at 5 years were 58% for the R-CHOP arm vs 46% for the CHOP arm.

NHL Study 9

• The safety and efficacy of rituximab was evaluated in a randomized, active-controlled, open-label, multicenter study in 823 patients with previously untreated DLBCL.

• Patients were randomly assigned 1:1 to receive either an anthracycline-containing chemotherapy regimen alone or in combination with rituximab. The main outcome measure was time to treatment failure, defined as time from randomization to the earliest of progressive disease, failure to achieve a complete response, relapse, or death.

• The median time to treatment failure was not reliably estimable for both arms (HR, 0.45; 2-sided P <.05). The OS estimates at 2 years were 95% for the R-chemotherapy arm vs 86% for the chemotherapy arm (HR, 0.40; 2-sided P <.05).

Chronic Lymphocytic Leukemia (CLL)

The safety and efficacy of rituximab were evaluated in two randomized (1:1) multicenter open-label studies comparing fludarabine and cyclophosphamide (FC) alone or in combination with rituximab (R-FC) for up to 6 cycles in patients with previously untreated CLL [CLL Study 1 (n=817)] or previously treated CLL [CLL Study 2 (n=552)].

Patients received fludarabine 25mg/m²/day and cyclophosphamide 250mg/m²/day on days 1, 2, and 3 of each cycle, with or without rituximab. In both studies, 71% of CLL patients received 6 cycles and 90% received at least 3 cycles of rituximab-based therapy. The main outcome measure for both studies was PFS, defined as the time from randomization to progression, relapse, or death, as determined by investigators (CLL Study 1) or an independent review committee (CLL Study 2). 

Results for CLL Study 1

• The median PFS was 39.8 months for the R-FC arm vs 31.5 months for the FC arm (HR, 0.56; 95% CI, 0.43-0.71; P <.01). The response rate was 86% (95% CI, 82-89) for the R-FC arm vs 73% (95% CI, 68-77) for the FC arm.

Results for CLL Study 2

• The median PFS was 26.7 months for the R-FC arm vs 21.7 months for the FC arm (HR, 0.76; 95% CI, 0.60-0.96; P =.02). The response rate was 54% (95% CI, 48-60) for the R-FC arm vs 45% (95% CI, 37-51) for the FC arm.

Exploratory subset analyses in CLL Studies 1 and 2 in elderly patients

CLL Study 1

• 572 patients aged <65yrs (HR for PFS, 0.52; 95% CI, 0.39-0.70)

• 245 patients aged ≥65yrs (HR for PFS, 0.62; 95% CI, 0.39-0.99)

• 736 patients aged <70yrs (HR for PFS, 0.51; 95% CI, 0.39-0.67)

• 81 patients aged ≥70yrs (HR for PFS, 1.17; 95% CI, 0.51-2.66)

CLL Study 2

• 313 patients aged <65yrs (HR for PFS, 0.61; 95% CI, 0.45-0.84)

• 233 patients aged ≥65yrs (HR for PFS, 0.99; 95% CI, 0.70-1.40)

• 438 patients aged <70yrs (HR for PFS, 0.67; 95% CI, 0.51-0.87)

• 108 patients aged ≥70yrs (HR for PFS, 1.22; 95% CI, 0.73-2.04)

Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) Study 1 (Induction Treatment of Adults with Active Disease)

• The randomized, double-blind, active-controlled, multicenter, non-inferiority study evaluated rituximab in 197 patients with active, severe GPA and MPA. The study was conducted in 2 phases - a 6 month remission induction phase and a 12 month remission maintenance phase.

• Patients were randomly assigned 1:1 to receive either rituximab 375mg/m² once weekly for 4 weeks or oral cyclophosphamide 2mg/kg daily for 3 to 6 months in the remission induction phase. Once remission was achieved or at the end of the 6 month remission induction period, the cyclophosphamide group received azathioprine to maintain remission. The rituximab arm did not receive additional therapy to maintain remission.

• The main outcome measure for both GPA and MPA patients was achievement of complete remission at 6 months defined as a BVAS/GPA of 0, and off glucocorticoid therapy.

• Results showed that 64% (95% CI, 54-73) of patients treated with rituximab achieved complete remission (CR) at 6 months vs 53% (95% CI, 43-63) of patients treated with cyclophosphamide (treatment difference, 11%; 95% CI, -3, 24).

• In the rituximab arm, 44% of patients achieved CR at 6 and 12 months, and 38% of patients achieved CR at 6, 12, and 18 months. In patients treated with cyclophosphamide (followed by azathioprine for maintenance of CR), 38% of patients achieved CR at 6 and 12 months, and 31% of patients achieved CR at 6, 12, and 18 months. 

GPA/MPA Study 1 (Follow Up Treatment of Adults with Active Disease who achieved disease control with other immunosuppressant)

• The open-label, prospective, multicenter, randomized, active-controlled study included 115 patients 21 years of age and older with GPA/MPA, who were randomly assigned 1:1 to receive azathioprine or non-US-licensed rituximab.

• The primary endpoint was the occurrence of major relapse (defined by the reappearance of clinical and/or laboratory signs of vasculitis activity that could lead to organ failure or damage, or could be life-threatening) through month 28.

• By month 28, major relapse occurred in 3 patients (5%) in the non-US-licensed rituximab group and 17 patients (29%) in the azathioprine group. 

• The observed cumulative incidence rate of first major relapse during the 28 months was lower in patients on non-US-licensed rituximab relative to azathioprine.