FDA approves first cancer radioimmunotherapy drug
June 1, 2002
FDA approves first cancer radioimmunotherapy drug
Therapy for Non-Hodgkin’s lymphoma
The Food and Drug Administration (FDA) recently approved the first in the class of radioimmunotherapy drugs for cancer therapy. 90Yttrium ibritumomab tiuxetan (Zevalin) is a novel anti-cancer radiopharmaceutical approved for patients with B-cell Non-Hodgkin’s lymphoma (NHL).
90Yttrium ibritumomab tiuxetan includes the monoclonal antibody ibritumomab (the mouse-based anti-CD20 monoclonal antibody parent of the chimeric antibody rituximab previously approved for treatment of NHL). The antibody is chemically bound to the therapeutic radioisotope 90Yttrium using the chemical linker tiuxetan. 90Yttrium ibritumomab tiuxetan has been approved for treatment of relapsed or refractory low-grade, follicular, or transformed B-cell NHL, including patients who are refractory to rituximab.
90Yttrium ibritumomab tiuxetan has been approved as part of a therapeutic regimen that uses a dose of rituximab (the cold monoclonal antibody) given just prior to the radioactive antibody, which improves the distribution of the radioactive antibody resulting in more radiation being delivered to the tumor. 90Yttrium ibritumomab tiuxetan targets tumor cells with a high dose of radiation, reducing the amount of radiation to the normal body organs.
"Zevalin is a novel way of treating cancer, in this case lymphoma," says Gregory A. Wiseman, MD, assistant professor of diagnostic radiology at Mayo Medical School and consultant in the department of diagnostic radiology at Mayo Clinic in Rochester, MN. Wiseman has been involved in the clinical trials of the drug.
"Many patients with low-grade Non-Hodgkin’s lymphoma will initially have a good response to chemotherapy, but will later relapse. Zevalin will be a good treatment option for those patients, an option that doesn’t seem to be affected by the fact that they have relapsed or are resistant to the chemotherapy. Many patients will still have a good response to the Zevalin."
90Yttrium ibritumomab tiuxetan treatment has an advantage over chemotherapy in that it can be completed in one week and can be given in an outpatient setting, says Joseph C. Hung, PhD, BCNP, director of nuclear pharmacy and PET radiochemistry facility and an associate professor of radiology at Mayo Medical School. "Normally, the chemotherapy would take about four to six months to complete."
The therapeutic regimen is administered in two parts. Patients first receive an intravenous infusion of rituximab followed by an infusion of the ibritumomab tiuxetan antitumor antibody linked to a low dose of 111Indium, a radioisotope used for imaging the biodistribution of the antibody. If the biodistribution of the ibritumomab tiuxetan antibody is normal, the patient is given the therapy one week later.
During the therapy, patients receive an infusion of rituximab again with a 90Yttrium beta-emitting therapeutic radioisotope attached. When the antibody binds the tumor cell, the attached 90Yttrium delivers radiation directly to the tumor cells.
The entire treatment is completed in one week. "Patients seem to tolerate the treatment quite well. They don’t have hair loss and generally don’t have nausea or vomiting," Wiseman says. "Patients like the fact that treatment does not require staying in the hospital, but rather can be given as an outpatient. The treatment is completed over a short period of time and since patients feel well, many return to their daily activities shortly after returning home."
Since 90Yttrium ibritumomab tiuxetan is a radiopharmaceutical, it will be new for many pharmacies, he says. "It’s similar to using radioactive iodine for treating thyroid cancer, but it does require an intravenous infusion."
Study results are positive
Researchers conducted four multicenter trials to demonstrate the safety and efficacy of 90Yttrium ibritumomab tiuxetan in treating NHL. In one trial, 57 patients who had failed chemotherapy and rituximab were treated with 90Yttrium ibritumomab tiuxetan. An overall response rate of 74% was achieved with the treatment, with 15% of subjects having a complete response.
A complete response to treatment means that physicians can no longer find any tumor cells in the patient during follow-up CT scans and lab tests, Wiseman explains. A partial response means that tumors are reduced in volume by at least 50%.
A second trial enrolled 143 patients who had relapsed or were not responding to chemotherapy but had not yet received rituximab. Patients were blindly randomized to receive 90Yttrium ibritumomab tiuxetan or standard dose rituximab. An overall response rate of 80% was obtained in the group treated with the 90Yttrium ibritumomab tiuxetan regimen (73 subjects), compared to 56% for the subjects receiving rituximab alone (70 subjects). Thirty percent of the 90Yttrium ibritumomab tiuxetan-treated patients experienced a complete response, compared to a 16% complete response rate for rituximab-treated subjects.
The 90Yttrium ibritumomab tiuxetan therapy, however, more toxic than rituximab, with the main side-effect being marrow toxicity and transient decreases in blood counts similar to those experienced with chemotherapy. Rituximab can have infusion-related side effects, including chills, fevers, hypotension, rash, and hives, Wiseman says. "These stop once the infusion is complete."
The 90Yttrium ibritumomab tiuxetan radio-labeled antibody doesn’t have any symptoms during infusion, he says. More than half of the patients in the clinical trials experienced significant reductions in blood cell counts, including white blood cells and platelets lasting for two to three weeks. Hemorrhages, though rarely fatal, and life-threatening infections occurred in a small number of patients. Because of these potential adverse effects, 90Yttrium ibritumomab tiuxetan is recommended only for patients who have relapsed after chemotherapy or rituximab and who have adequate bone marrow reserves.
Additional studies of 90Yttrium ibritumomab tiuxetan have been planned or are under way, Wiseman says. Some studies are looking at using it in bone marrow transplantation for NHL and to see if it would be useful in more aggressive NHL. Wiseman is involved in a study to see if physicians can use two doses of the 90Yttrium ibritumomab tiuxetan treatment. "In the study, we are giving a treatment to the patients. When their blood counts recover, we give them a second dose of treatment to see the safety of giving two treatments, to see if patients will have a better and longer response of their lymphoma to treatment."
IDEC Pharmaceuticals announced at the end of March that it was taking orders for 90Yttrium ibritumomab tiuxetan. Its cost is similar to other biologics used in the treatment of lymphoma, Wiseman says.
The Bexxar factor
Another radioimmunotherapy drug that is before the Food and Drug Administration (FDA) for approval is 131Iodine tositumomab (Bexxar). 131Iodine tositumomab also has been studied for the treatment of low-grade or transformed low-grade Non-Hodgkin’s lymphoma (NHL), and it uses the same type of antibody, the anti-CD20, to target the cancer cell as 90Yttrium ibritumomab tiuxetan (Zevalin).
Tositumomab, however, uses the I-131 radioisotope rather than 90Yttrium. "90Yttrium is a beta emitter only while 131Iodine is a beta emitter and a gamma emitter as well," says Gregory A. Wiseman, MD, assistant professor of diagnostic radiology at Mayo Medical School and consultant in the department of diagnostic radiology at Mayo Clinic in Rochester, MN. "The gamma emission can be useful for imaging the radiolabeled antibody directly, but also makes the radiation safety more difficult in terms of radiation exposure of the health care workers and the patient family members."
In March, tositumomab hit a snag with the FDA. Tositumomab and the manufacturer Corixa Corp. received a letter from the FDA regarding the Biological License Application (BLA) for tositumomab. (Tositumomab is being co-developed in the United States by Corixa and GlaxoSmithKline.) In the letter, the FDA stated that it believed additional data would be required to approve tositumomab and gave Corixa the options of amending its application, notifying the agency of its intent to file an amendment, withdrawing the application, or requesting an opportunity for a hearing on whether there are grounds for denying approval of the application.
Corixa announced on March 25 that it intended to amend the BLA. Corixa and GlaxoSmithKline also announced that they had formally requested a meeting with the FDA to discuss the complete review letter and potential next steps regarding the application.
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