ZEVALIN Kit for radiopharmaceutical preparations for infusion Ref.[11002] Active ingredients:

Pharmacotherapeutic group: Various therapeutic radiopharmaceuticals
ATC code: V10XX02

Mechanism of action

Ibritumomab tiuxetan is a recombinant murine IgG1 kappa monoclonal antibody specific for the B-cell antigen CD20. Ibritumomab tiuxetan targets the antigen CD20 which is located on the surface of malignant and normal B-lymphocytes. During B-cell maturation, CD20 is first expressed in the midstage of B-lymphoblast (pre-B-cell), and is lost during the final stage of B-cell maturation to plasma cells. It is not shed from the cell surface and does not internalise on antibody binding.

[⁹⁰Y]-radiolabelled ibritumomab tiuxetan binds specifically to CD20-expressing B-cells, including malignant cells. The isotope yttrium-90 is a pure β-emitter and has a mean path length of about 5 mm. This results in the ability to kill both targeted and neighbouring cells.

The conjugated antibody has an apparent affinity constant for the CD20 antigen of approximately 17 nM. The binding pattern is very restricted, with no cross-reactivity to other leukocytes or to other types of human tissue.

Rituximab pretreatment is necessary to clear circulating B-cells, enabling ibritumomab tiuxetan [⁹⁰Y] to deliver radiation more specifically to the lymphoma B-cells. Rituximab is administered in a reduced dose when compared with the approved monotherapy.

Pharmacodynamic effects

Treatment with [⁹⁰Y]-radiolabelled Zevalin also leads to depletion of normal CD20+ B-cells. Pharmacodynamic analysis demonstrated that this was a temporary effect; recovery of normal B-cells began within 6 months and median counts of B-cells were within normal range within 9 months after treatment.

Clinical efficacy and safety

The safety and efficacy of the Zevalin therapeutic regimen were evaluated in two multi-center trials enrolling a total of 197 subjects. The Zevalin therapeutic regimen was administered in two steps (see 4.2). The efficacy and safety of a variation of the Zevalin therapeutic regimen employing a reduced dose of ibritumomab tiuxetan [⁹⁰Y] was further defined in a third study enrolling a total of 30 patients who had mild thrombocytopenia (platelet count 100,000 to 149,000 cells/mm³).

Study 1 was a single-arm study of 54 patients with relapsed follicular lymphoma refractory to rituximab treatment. Patients were considered refractory if their last prior treatment with rituximab did not result in a complete or partial response, or if time to disease progression (TTP) was <6 months. The primary efficacy endpoint of the study was the overall response rate (ORR) using the International Workshop Response Criteria (IWRC). Secondary efficacy endpoints included time to disease progression (TTP) and duration of response (DR). In a secondary analysis comparing objective response to the Zevalin therapeutic regimen with that observed with the most recent treatment with rituximab, the median duration of response following the Zevalin therapeutic regimen was 6 vs. 4 months. Table 1 summarizes efficacy data from this study.

Study 2 was a randomized, controlled, multicenter study comparing the Zevalin therapeutic regimen versus treatment with rituximab. The trial was conducted in 143 rituximab-naïve patients with relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma (NHL), or transformed B-cell NHL. A total of 73 patients received the Zevalin therapeutic regimen, and 70 patients received rituximab given as an intravenous infusion at 375 mg/m² weekly times 4 doses. The primary efficacy endpoint of the study was to determine the ORR using the IWRC (see Table 2). The ORR was significantly higher (80% vs. 56%, p = 0.002) for patients treated with the Zevalin therapeutic regimen. The secondary endpoints, duration of response and time to progression, were not significantly different between the two treatment arms.

Table 2. Summary of Efficacy Data in patients with relapsed/refractory low-grade or follicular non-Hodgkin’s lymphoma (NHL), or transformed B-cell NHL:

¹ IWRC: International Workshop response criteria
² CRu: Unconfirmed complete response
³ Estimated with observed range.
⁴ Duration of response: interval from the onset of response to disease progression.
⁵ “+” indicates an ongoing response.
⁶ Time to Disease Progression: interval from the first infusion to disease progression.

Study 3 was a single arm study of 30 patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL who had mild thrombocytopenia (platelet count 100,000 to 149,000 cells/mm³). Excluded from the study were patients with 25% lymphoma marrow involvement and/or impaired bone marrow reserve. Patients were considered to have impaired bone marrow reserve if they had any of the following: prior myeloablative therapy with stem cell support; prior external beam radiation to >25% of active marrow; a platelet count <100,000 cells/mm³; or neutrophil count <1,500 cells/mm³. In this study, a modification of the Zevalin therapeutic regimen with a lower [⁹⁰Y]-Zevalin activity per body weight (11 MBq/kg) was used. Objective, durable clinical responses were observed [67% ORR (95% CI: 48-85%), 11.8 months median DR (range: 4-17 months)] and resulted in a greater incidence of haematologic toxicity (see 4.8) than in Studies 1 and 2.

Study 4 investigated the efficacy and safety of Zevalin consolidation in patients with advanced-stage follicular lymphoma responding to first-line chemotherapy. Major inclusion criteria were: CD20+ grade 1 or 2 follicular lymphoma; stage III or IV at diagnosis; normal peripheral blood cell counts; < 25% bone marrow involvement; age ≥ 18 yrs; and complete response (CR/Cru) or partial response (PR) after first-line chemotherapy determined by physical examination, CT scans and bone marrow biopsy. After completing induction therapy, patients were randomized to receive either Zevalin (250 mg/m² rituximab on day -7 and on day 0 followed on day 0 by Zevalin 15 MBq/kg body weight; maximal dose 1200 MBq; [n=208]) or no further treatment (control; n=206). Induction therapies included CVP n=106, CHOP (-like) n=188, fludarabine combinations n=22, chlorambucil n=39 and rituximab-chemotherapy combinations n=59. Median progression free survival (PFS) was calculated at a median follow-up of 2.9 years. PFS increased from 13.5 months (control) to 37 months (Zevalin; p<0.0001; HR 0.465). For patient subgroups in PR or CR after induction, median PFS was 6.3 vs 29.7 months (p<0.0001; HR 0.304) and 29.9 vs 54.6 months (p=0.015; HR 0.613), respectively. After Zevalin consolidation, 77% of patients in PR after induction therapy converted to CR. Patients whose response status changed after Zevalin from PR to CR showed a significantly longer median progression free survival time (986 days) compared to those patients who remained in PR (median progression free survival time of 460 days, p=0.0004). In total, 87% of patients were in CR(u); 76% in CR and 11% in CRu.