PRIMA Trial

RITUXAN maintenance following first-line R-CHEMO—proven in a Phase III trial of more than 1,000 follicular NHL patients

PRIMA TRIAL DESIGN1,2

Chart: Prima Trial Design
  • To ensure that all patients received an equal number of courses of RITUXAN prior to maintenance randomization, an additional 2 courses of RITUXAN were given to R-CHOP– and R-FCM–treated patients. For the R-CHOP patients, the 2 additional courses were given on Day 1 of Cycles 7 and 8; for the R-FCM patients, the 2 additional courses were given on Day 15 of Cycles 1 and 4.2
  • PRIMA=Primary RItuximab and MAintenance; R=RITUXAN; NHL=non-Hodgkin’s lymphoma; CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisone; CVP=cyclophosphamide, vincristine, and prednisone; FCM=fludarabine, cyclophosphamide, and mitoxantrone; PFS=progression-free survival; PR=partial response; CR=complete response.
  • The PRIMA dosing schedule was chosen based on its potential to maintain a target serum level of RITUXAN3
  • This once-every-2-months dosing schedule was also supported by data from earlier Phase II clinical trials4,5

Patient population was diverse and well balanced across both arms

PATIENT CHARACTERISTICS2

Baseline characteristics before induction* RITUXAN†
(n=505) 		Observation†
(n=513)
Age Median (range) 57
(26-79) 		55
(22-84)
Sex Female Male 47%
53% 		49%
51%
Bone marrow involvement Involved Not involved Unspecified Not done 54%
43%
2%
<1% 		56%
42%
1%
2%
Extranodal involvement <2 sites ≥2 sites 57%
43% 		54%
46%
ECOG performance status 0 1 2 64%
32%
4% 		66%
30%
3%
FLIPI score ≤1 2 ≥3 21%
36%
43% 		21%
36%
42%
Induction therapy R-CHOP R-CVP R-FCM 76%
22%
3% 		75%
22%
3%
  • *For patients (N=1,018) who were randomized to the maintenance portion of the trial.2
  • †Percentages are rounded and may not add up to 100%.
  • ECOG=Eastern Cooperative Oncology Group; FLIPI=Follicular Lymphoma International Prognostic Index.
  • The PRIMA trial’s diverse patient population included2:
    • Patients with bulky disease—98% of the PRIMA population had bulky disease prior to induction therapy
    • Higher-risk patients—43% had a FLIPI score of ≥3
    • Lower-risk patients—57% had a FLIPI score of ≤2

RITUXAN maintenance following first-line R-CHEMO nearly doubled the likelihood of remaining progression-free at 2-year median follow-up

PFS AT 2-YEAR MEDIAN FOLLOW-UP1,2

Chart: PFS at 2-Year Median Follow-Up
  • CI=confidence interval.

In a Kaplan-Meier PFS curve, when the patient population gets smaller, either due to availability for analysis or progression, a single event can result in a drastic drop in the curve. PFS assessment after 27 months is based on <10% of the patient population and the plot cannot be used to reliably predict PFS beyond this time point.

A prespecified interim analysis demonstrated the superiority of RITUXAN maintenance vs observation following first-line R-CHEMO. FDA approval was based on an independent review committee (IRC) assessment of the study results2:

  • RITUXAN maintenance provided a 46% reduction in the risk of progression, relapse, or death (p<0.0001)2
  • RITUXAN maintenance significantly improved PFS at 2 years—78% vs 62%2
    • Results from the investigator’s analysis showed a similar 2-year PFS improvement in the RITUXAN maintenance arm—82% vs 66% (p<0.0001; HR: 0.50; 95% CI: 0.39–0.64)

Safety for single-agent RITUXAN as maintenance for follicular NHL after first-line RITUXAN-based chemotherapy

  • Detailed safety data collection was limited to Grade ≥2 infections, Grade ≥3 adverse reactions, and serious adverse reactions
  • The most frequently reported adverse reaction was infections. In patients receiving RITUXAN as single-agent maintenance therapy following RITUXAN plus chemotherapy, infections were reported more frequently compared with the observation arm (37% vs 22%). Most infections reported with RITUXAN maintenance were Grade 2
  • The most common Grade 3-4 adverse reactions occurring at a higher incidence (≥2%) in the RITUXAN arm than in the observation arm were infections (4% vs 1%) and neutropenia (4% vs <1%)

References:
  1. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2012.
  2. Data on file, Genentech, Inc.
  3. Berinstein NL, Grillo-López AJ, White CA, et al. Association of serum rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol. 1998;9:995-1001.
  4. Ghielmini M, Hsu Schmitz SF, Cogliatti SB, et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly ×4 schedule. Blood. 2004;103:4416-4423.
  5. Gordan LN, Grow WB, Pusateri A, et al. Phase II trial of individualized rituximab dosing for patients with CD20-positive lymphoproliferative disorders. J Clin Oncol. 2005;23:1096-1102.

Indications

RITUXAN® (Rituximab) is indicated for the treatment of patients with:

  • Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent
  • Previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy and, in patients achieving a complete or partial response to RITUXAN in combination with chemotherapy, as single-agent maintenance therapy
  • Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after first-line CVP chemotherapy
  • Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens
  • Previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide (FC)

RITUXAN is not recommended for use in patients with severe, active infections.

Important Safety Information

WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)

Infusion Reactions: RITUXAN administration can result in serious, including fatal, infusion reactions. Deaths within 24 hours of RITUXAN infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue RITUXAN infusion and provide medical treatment for Grade 3 or 4 infusion reactions.

Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-Hodgkin's lymphoma (NHL) with RITUXAN monotherapy.

Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving RITUXAN.

Progressive Multifocal Leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving RITUXAN.

Warnings and Precautions

RITUXAN has also been associated with other serious and/or fatal adverse reactions. These include

  • hepatitis B reactivation with fulminant hepatitis; hepatic failure resulting in death
  • serious, including fatal, bacterial, fungal, and new or reactivated viral infections
  • cardiovascular events, including serious or life-threatening cardiac arrhythmias
  • severe, including fatal, renal toxicity
  • abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving RITUXAN in combination with chemotherapy

Additional Important Safety Information

  • The most frequent Grade 3 or 4 adverse reactions observed in NHL were cytopenias, including lymphopenia. The most common adverse reactions of RITUXAN (incidence ≥25%) observed in clinical trials of patients with NHL were infusion reactions, fever, lymphopenia, chills, infection, and asthenia. The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. These infusion reactions typically resolved with slowing or interruption of the infusion and with supportive care
  • The most common adverse reactions of RITUXAN (incidence ≥25%) observed in clinical trials of patients with CLL were infusion reactions and neutropenia. Infusion-related adverse reactions occurring during or within 24 hours of the start of infusion included nausea, pyrexia, chills, hypotension, vomiting, and dyspnea
  • Most CLL patients treated with R-FC experienced at least one Grade 3 or 4 adverse reaction. The Grade 3 or 4 adverse reactions observed more frequently with R-FC compared with FC alone were neutropenia, leukopenia, febrile neutropenia, thrombocytopenia, infusion reactions, pancytopenia, hypotension, and hepatitis B
  • In clinical trials, CLL patients 70 years of age or older who received R-FC had more Grade 3 and 4 adverse reactions compared with younger CLL patients who received the same treatment

For additional safety information, please see the full prescribing information, including BOXED WARNINGS and Medication Guide.

Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.