ROCHESTER, Minnesota—A phase-III clinical trial has shown that 73% of B-cell non-Hodgkin’s lymphoma (NHL) patients respond to the radioimmunotherapy ibritumomab tiuxetan (Zevalin) vs 47% for rituximab(Drug information on rituximab) (Rituxan). The study concluded that ibritumomab tiuxetan (Zevalin) is not only safe and effective, but the objective response rates achieved with it are statistically superior to those achieved with rituximab alone.
Ibritumomab tiuxetan is a murine anti-CD20 monoclonal antibody attached to the radioactive isotope yttrium 90. Data on trials of ibritumomab tiuxetan have been submitted to the Food and Drug Administration. Although the trials are closed, patients are being followed.
In the trial of 143 patients, the complete response (CR) rate was 30% for ibritumomab tiuxetan and 16% for rituximab. The response rates were classified by a LEXCOR (Lymphoma Experts Confirmation of Response) panel blinded to the study arm and investigator assignment of response, according to lead researcher and hematologist Thomas Witzig, MD, of Mayo Clinic in Rochester, Minnesota.
"The study provides another bit of evidence that adding yttrium 90 to the anti-CD20 antibody does seem to provide an increased response rate," Dr. Witzig said. The final response rates in this phase-III trial were very similar to the individual response rates of ibritumomab tiuxetan and rituximab found in separate phase-II trials, Dr. Witzig added.
Stratified by Histology
Patients were stratified by histology into a group of 73 patients in the ibritumomab tiuxetan arm and 70 patients in the rituximab arm of the study. The rituximab patients were given a 375 mg/m2 weekly dose of the drug for 4 weeks. The ibritumomab tiuxetan regimen consisted of day-0 rituximab 250 mg/m2 followed by 5 mCi 111indium-labeled ibritumomab tiuxetan and day-7 rituximab 250 mg/m2 followed by 0.4 mCi/kg ibritumomab tiuxetan.
Out of the 73 patients who received ibritumomab tiuxetan, 53 responded. Of the 70 rituximab patients, 33 had remissions after therapy. The total median duration of response and time to progression had not been reached for either arm. Estimates of the response duration were not statistically different at 10.9 months for ibritumomab tiuxetan vs 11.5 months for rituximab.
At the time of the presentation, 31% to 32% of the ibritumomab tiuxetan patients had an ongoing response, Dr. Witzig reported.
Estimates of time to next anticancer therapy was a median of 15.2 months for the rituximab group, but had not been reached for the ibritumomab tiuxetan group. For those patients who had progressed, the median time to next treatment was 11.5 months for the ibritumomab tiuxetan group compared to 7.8 months for the rituximab group, Dr. Witzig added.
The investigators also analyzed the time to progression in patients who had a complete response vs a partial remission (PR). "There’s no difference in time to progression when you compare CR and PR patients in the rituximab group," Dr. Witzig said. "But in ibritumomab tiuxetan patients with a partial response, there’s a continuous drop-off in time to progression."
Quality-of-Life Issues
Ibritumomab tiuxetan proved to be a safe drug in this clinical trial, and adverse events were primarily hematologic, transient, and reversible. Thirty-two percent of ibritumomab tiuxetan patients developed grade 4 neutropenia and 5% developed grade 4 thrombocytopenia. Five patients (7% of the ibritumomab tiuxetan group) required hospitalization for infection. Two percent of patients developed human antibodies to the murine antibody (HAMA response).
The patients in each arm of the trial had very similar characteristics. Median age was 60 years in the ibritumomab tiuxetan group vs 57 years in the rituximab group. Patients had received a median of two prior treatment regimens. In the ibritumomab tiuxetan group, 42% had bone marrow involvement vs 34% for the rituximab group.
Patients in the ibritumomab tiuxetan arm had been resistant to their last chemotherapy treatments about half the time, and 90% of these patients had stage III/IV disease. About 75% of the ibritumomab tiuxetan patients had follicular histology.
All patients were asked about quality-of-life issues on the Functional Assessment of Cancer Therapy General (FACT-G) survey. In the ibritumomab tiuxetan group, patients completed the FACT-G at baseline, 1 day after infusion and at 1, 2, and 3 months afterward. The survey was to be completed by patients in the rituximab arm at baseline, after the fourth rituximab infusion, and at weeks 4 and 12, and at months 6, 9, and 12 post-treatment.
Quality-of-life scores improved for patients in both arms. The difference between scores on the Fact-G questionnaire at the beginning and end of therapy, however, was significant only for the ibritumomab tiuxetan group.
"The study worked to confirm our main hypotheses," Dr. Witzig concluded. "With the radiolabeled conjugate, Zevalin patients had a higher response rate than with rituximab alone."
