FDA Approves Zevalin for Use With Rituxan in Refractory NHL Patients

ROCKVILLE, Maryland—For the first time, the US Food and Drug Administration has approved the use of a radioisotope attached to a monoclonal antibody for the treatment of cancer.

The agency granted marketing approval to the radioimmunotherapy Zevalin (ibritumomab tiuxetan, IDEC Pharmaceuticals) in combination with Rituxan (rituximab) for use in treating patients with relapsed or refractory low-grade follicular or transformed B-cell non-Hodgkin’s lymphoma (NHL) who have failed to respond to standard chemotherapy or to treatment with Rituxan alone.

Both Zevalin and Rituxan are monoclonal antibodies that target normal and malignant B cells via the CD20 antigen and significantly reduce tumor size. The antibody in Zevalin, however, is bound to one of two radioisotopes: indium-111 or yttrium-90.

The novel combination regimen is administered in two parts. Patients first receive Rituxan, which is followed by a Zevalin treatment in which the monoclonal antibody is linked to a low-dose of indium-111. This Zevalin dose is used as a screening procedure.

Those patients whose tumors have been properly targeted by Zevalin go on to a second round of infusions 7 to 9 days later. A patient again receives Rituxan, followed by a different form of Zevalin in which the antibody is bound to yttrium-90, a more powerful radioisotope that can provide a treatment benefit.

"Zevalin represents a major advance in the treatment of certain non-Hodgkin’s lymphomas, especially among patients who have become refractory to other treatment options," said Thomas E. Witzig, MD, a hematologist at the Mayo Clinic, Rochester, Minnesota, and a leader in the clinical trials of the drug. "Unlike standard chemotherapy, which is given over as many as 4 months, Zevalin can be administered in an outpatient setting over 8 days with approximately 12 weeks of follow-up." According to IDEC, CD20-negative progenitor cells generally replenish normal B cells killed by Zevalin within 6 to 9 months.

The FDA granted Zevalin both full and accelerated approval, as recommended by the Oncologic Drugs Advisory Committee last September. The accelerated approval requires IDEC to conduct further studies to demonstrate the safety and efficacy of the drug in relapsed or refractory patients who have not yet received Rituxan.

The FDA decision followed a review of two multicenter, phase III studies conducted in the United States. In one trial, the basis for full FDA approval, 54 patients who were no longer responding to chemotherapy or Rituxan received the combination therapy. The study’s overall response rate was 74%, and 15% had a complete response.

The second study, the basis for accelerated approval, enrolled 143 patients who were not responding to chemotherapy but had not undergone Rituxan treatment. The Rituxan-Zevalin therapy patients showed an 80% overall response rate, compared with a 56% rate for those who received Rituxan alone.

Although the patients treated with Zevalin had a 2-month longer duration of response than those receiving Rituxan alone, the study did not determine whether the addition of Zevalin prolonged survival over Rituxan alone. IDEC is continuing to study that question.

Toxicity Concerns

The Rituxan-Zevalin treatment was more toxic than Rituxan alone. "More than half of the patients in the clinical trials experienced serious reductions in blood cell counts, including white blood cells and platelets, lasting for 3 to 4 weeks," the FDA said in announcing its approval of Zevalin. "Hemorrhages, some fatal, and life-threatening infections occurred in a small number of patients."

The agency gave the high rate of adverse events as the reason for limiting Zevalin’s use to patients who had already failed other therapies.

According to IDEC, data from 349 patients show that the most serious adverse reactions of the Zevalin regimen are severe infusion reactions—including hypotension, angioedema, hypoxia, and bronchospasm—and severe and prolonged thrombocytopenia and neutropenia. Sixty-one percent of patient had platelet counts less than 50,000 cells/µL and 57% of patients had absolute neutrophil counts less than 1,000 cells/µL.