ODAC Recommends Approval of Radiolabeled Zevalin

BETHESDA, Maryland—The Oncologic Drugs Advisory Committee (ODAC) has unanimously recommended that the Food and Drug Administration approve the marketing of Zevalin (ibritumomab tiuxetan, IDEC Pharmaceuticals) for the treatment of patients with rituximab (Rituxan)-refractory follicular, B-cell non-Hodgkin’s lymphoma (NHL).

However, by a 10-to-6 vote, the committee failed to recommend that the agency fully approve Zevalin for the treatment of patients who have not failed rituximab therapy, including those with relapsed or refractory low-grade follicular NHL or CD20-positive transformed B-cell NHL. For this indication, the committee suggested that the FDA consider approval under the agency’s accelerated approval regulations.

Zevalin is a murine monoclonal antibody linked by a chelating agent to the radioactive isotope yttrium-90, and it is intended as a complementary drug to rituximab. Both monoclonal antibodies target the CD-20 surface antigen expressed on B-lineage tumor cells.

A Two-Part Process

Administering Zevalin is a two-part process. A patient first receives a single infusion of rituximab (250 mg/m²), followed by indium-111-labeled Zevalin for imaging. A week later, the patient gets a second infusion of rituximab at the same dose, followed by a therapeutic infusion of Zevalin (2 mg of antibody labeled with 0.3 or 0.4 mCi/kg of yttrium-90, depending on the patient’s baseline platelet count). The maximum Zevalin dose for any patient is 32 mCi.

A hospital’s nuclear pharmacy prepares the active drug from a kit obtained from IDEC that contains the monoclonal antibody. The pharmacy then labels the monoclonal antibody with the yttrium radioisotope obtained from a separate source. The mixture remains stable for about 8 hours.

"If the committee recommends approval of this product, you should be aware there are some outstanding manufacturing issues," said Marjorie Shapiro, PhD, of the FDA’s product review team for Zevalin.

Study 106-04

IDEC presented data from two phase III pivotal trials, plus two phase I/II trials and one phase II study in support of Zevalin. Christine A. White, MD, IDEC vice president for medical affairs, stressed the promise of the drug. "Zevalin represents a new class of targeted therapy that is a well-tolerated outpatient therapy completed in 8 days."

Study 106-04 was a controlled, randomized trial carried out in 143 patients (73 Zevalin, 70 rituximab) at 27 US institutions. Patients received either the Zevalin regimen or rituximab (375 mg/m² weekly for 4 weeks) The primary endpoint was overall response rate. Most of the patients had follicular NHL, 75% in the Zevalin arm and 83% in the control group.

The company reported an overall response rate of 73% in the Zevalin patients vs 47% for the rituximab arm, a significant difference (P = .002). The overall response rate among the 113 follicular NHL patents was 76% for the Zevalin group and 47% for the rituximab patients, again, a significant finding with the same P value.

Zevalin patients had an 18% complete response rate vs 11% for those treated with rituximab, but this difference was not significant. In each arm, 4% of patients had a clinical complete response.

There was no statistical difference between the two arms in duration of response, duration of response by histology, or time to progression. Follicular NHL patients showed a statistically favorable trend in time to progression and time to next therapy.

Study 106-06

Study 106-06 was a nonrandomized trial of Zevalin carried out in 54 rituximab-refractory follicular NHL patients at 17 US institutions using the same Zevalin regimen as study 106-04. The primary endpoint was an overall response rate of at least 35%.

The 54 patients had an overall response rate of 59%, with 4% complete responders. The median duration of response was 7.7 months (range, 2.3 to 24.9).

Dr. White presented integrated safety data on 349 patients treated in Zevalin trials. Nonhematologic adverse events numbered 279, of which 39 were grade 3 or 4. Asthenia was the most common, occurring in 35.2% of patients. Other events included nausea (24.6%), chills (20.9%), and fever (13.2%). In the pivotal randomized phase III trial, 48% of the Zevalin patients suffered asthenia vs 41% of the rituximab therapy group.

Hematologic adverse events among the 349 patients were of more consequence. Among those receiving a Zevalin dose of 0.4 mCi/kg, 28% suffered grade 3 and 30% had grade 4 neutropenia; 52% had grade 3 and 10% had grade 4 thrombocytopenia; and 14% had grade 3 and 3% had grade 4 anemia.

Among patients getting a dose of 0.3 mCi/kg, grade 3 and 4 events for Zevalin and rituximab were, respectively, 40% and 35% for neutropenia, 66% and 14% for thrombocytopenia, and 12% and 8% for anemia.

The incidence of infection/febrile neutropenia in the 349 patients was 29%; 5% of the patients suffered grade 3 or 4 events. In the randomized phase III trial, the incidence was 43% overall, and 7% grade 3 or 4 for the Zevalin group vs 20% and 0.0% in the rituximab arm.

"Grade 3 and 4 toxicities correlated with the percent of bone marrow involvement, which is not surprising," Dr. White said. "They also correlated with the number of prior therapies and whether the patients had received purine analogs in the past."

During questions to the company by ODAC members, George W. Sledge, Jr., MD, professor of medicine and pathology, Indiana University School of Medicine, noted that the committee usually requires more than a positive response rate to recommend a drug’s approval. "This committee always wrestles with the issue of clinical benefit," he said. "What is the clinical benefit here?"

Thomas Witzig, MD, of the Mayo Clinic, who has participated in several Zevalin trials, replied: "The big clinical benefit is that it’s a single-dose therapy. These patients are all heavily pretreated; they have had many chemotherapies. Now they come in and get a treatment with virtually no sides effects such as nausea, vomiting, and hair loss, and the next day they go back to work and back to their normal activities."

Added Sandra Horning, MD, of Stanford University, "Patients with follicular lymphoma are actually living longer without a defined curable therapy."

The FDA’s review team generally agreed with IDEC’s interpretation of the study findings. "In general, Zevalin therapy has demonstrable and durable antitumor activity in subjects," said Philippe Bishop, MD, who presented its findings. He cautioned, however, that given the small numbers in the studies, FDA could reach no definitive conclusions about the drug’s effect on patients with transformed disease and other types of lymphoma.

Alexandra M. Levine, MD, professor of medicine, University of Southern California, and a voting consultant to the committee, reinforced Dr. Bishop’s concern. "In addition to the fact the numbers are just too small, their data show that rituximab is superior to Zevalin in transformed patients, if you believe these small numbers," she said.

Dr. Bishop also noted concerns about the significantly greater hematologic side effects associated with Zevalin, compared with rituximab. "Overall, Zevalin is characterized by a higher incidence of cytopenias," he said.

In the end, committee members agreed that Zevalin is an effective active agent in patients with follicular NHL, but recommended its approval for use only in rituximab-refractory patients.