ON JULY 30, 2018, the radiotherapeutic agent iobenguane I-131 (Azedra) was approved for the treatment of adult and pediatric patients (aged ≥ 12 years) with iobenguane scan–positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma who require systemic anticancer therapy.^1,2

Supporting Efficacy Data

APPROVAL WAS based on the findings of a multicenter trial of 74 patients aged ≥ 12 years with iobenguane scan–positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma.² Of the 74 patients receiving a dosimetric dose, 68 received at least 1 therapeutic dose, and 50 patients received 2 therapeutic doses administered at least 90 days apart. The dosimetric dose was 185 MBq to 222 MBq (5–6 mCi) for patients weighing more than 50 kg and 3.7 MBq/kg (0.1 mCi/kg) for patients weighing 50 kg of less. The therapeutic dose was 18,500 MBq (500 mCi) for patients weighing more than 62.5 kg and 296 MBq/kg (8 mCi/kg) for patients weighing 62.5 kg or less.

Among the 68 patients, the median age was 55 years (range = 16–72 years), 57% were male, and 75% were white. For the primary tumor diagnosis, 78% had pheochromocytoma, 21% had paraganglioma, and 1% had both. Overall, 50% of patients with imaging studies had lung or liver metastases and 61% had bone metastases. A total of 88% had prior surgery, 50% received prior external radiation, 31% received prior chemotherapy, and 15% received prior kinase inhibitors. The median number of prior therapies was 2 (range = 0–7).

Of the 68 evaluable patients, 17 (25%) had at least a 50% reduction in all antihypertensive medication for at least 6 months. Tumor response (on Response Evaluation Criteria in Solid Tumors version 1.0) was observed in 15 patients (22%), with a response duration of at least 6 months in 53% of responders.

How It Works

IOBENGUANE I -131 is an I-131–labeled iobenguane. Iobenguane is similar in structure to the neurotransmitter norepinephrine and is subject to the same uptake and accumulation pathways as norepinephrine. Iobenguane is taken up by norepinephrine transporters in adrenergic nerve terminals and accumulates in adrenergically innervated tissues, such as the heart, lungs, adrenal medulla, salivary glands, liver, and spleen, as well as in tumors that originate in the neural crest.

Pheochromocytoma and paraganglioma are tumors of neural crest origin that express high levels of cell-surface norepinephrine transporters. Following intravenous administration, iobenguane I-131 is taken up by and accumulates within pheochromocytoma and paraganglioma cells; radiation resulting from radioactive decay of I-131 causes cell death and tumor necrosis.

How It Is Used

IOBENGUANE I-131 is a radiopharmaceutical that should be used by or under the control of physicians who are qualified by specific training and experience in the safe use and handling of radiopharmaceuticals and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radiopharmaceuticals.

Iobenguane I-131 is administered in an initial dosimetric dose, followed by two therapeutic doses that are adjusted based on dosimetry. The recommended dosimetric dose is 185 to 222 MBq (5–6 mCi) in patients weighing more than 50 kg and 3.7 MBq/kg (0.1 mCi/kg) in those weighing 50 kg or less. The recommended therapeutic dose for both therapeutic doses is 18,500 MBq (500 mCi) for patients weighing more than 62.5 kg and 296 MBq/kg (8 mCi/kg) for those weighing 62.5 kg or less. If necessary, the therapeutic doses should be adjusted based on the results of radiation dose estimates from dosimetry. The two therapeutic doses are given 90 days apart.

Pregnancy status must be verified prior to treatment with this agent. Treatment should not be given if the platelet count is less than 80,000/μL or the absolute neutrophil count is less than 1,200/μL. Thyroid blockade must be performed, with inorganic iodine started at least 24 hours before and continuing for 10 days after each iobenguane I-131 dose. Hydration must be performed, with patients instructed to increase fluid intake to at least 2 L/d, starting at least 1 day before and continuing for 1 week after each dose to minimize irradiation to the bladder.

Drugs that reduce catecholamine uptake or deplete catecholamine stores (eg, central nervous system stimulants or amphetamines, norepinephrine and serotonin-reuptake inhibitors, alpha agonists or alpha/beta agonists) must be discontinued for at least 5 half-lives before administration of either the dosimetry dose or a therapeutic dose of iobenguane I-131 and should not be given for at least 7 days after each dose. Antiemetics should be given 30 minutes prior to each dose.

Product labeling provides detailed instructions on dosimetry, therapeutic dose adjustment, and absorbed-dose threshold values for radiation toxicity in critical organs. Product labeling provides specific instructions for dose modification for myelosuppression and pneumonitis.

Safety Profile

SAFETY DATA ARE from 88 patients in 2 studies who received at least 1 therapeutic dose of iobenguane I-131, including 50 who received 2 therapeutic doses. Patients with evidence of liver dysfunction, history of liver disease, or severe renal impairment were excluded from the studies, as were patients who had received external-beam radiation therapy to more than 25% of the bone marrow, whole-body radiotherapy, or any systemic radiotherapy resulting in myelosuppression within 3 months of study entry.

The most common nonhematologic adverse events of any grade included nausea (78%), fatigue (71%), vomiting (58%), and dry mouth (48%). The most common grade 3 or 4 adverse events were lymphopenia (78%), neutropenia (59%), thrombocytopenia (50%), fatigue (26%), anemia (24%), increased international normalized ratio (18%), nausea (16%), dizziness (13%), hypertension (11%), and vomiting (10%). Treatment was discontinued due to adverse events in 12% of patients, with causes including thrombocytopenia, anemia, lymphopenia, nausea, vomiting, and multiple hematologic adverse events. Myelodysplastic syndrome (MDS) or acute leukemia occurred in 6.8% of patients.

Iobenguane I-131 carries warnings/precautions for risk from radiation exposure; myelosuppression; secondary MDS, leukemia, and other malignancies (time to development of MDS or acute leukemia has ranged from 12 months to 7 years); hypothyroidism; elevations in blood pressure; renal toxicity; pneumonitis; embryofetal toxicity; and infertility. Blood cell counts must be monitored during treatment with this agent. In addition, hypothyroidism and thyroid-stimulating hormone levels must be monitored before starting treatment and annually thereafter. Blood pressure must be monitored frequently during the first 24 hours after each therapeutic dose. Renal function must be monitored during and after treatment. Patients must be advised not to breastfeed while receiving iobenguane I-131. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves iobenguane I 131 for rare adrenal gland tumors. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm615157.htm. Accessed November 8, 2018.

2. Azedra (iobenguane I 131) injection prescribing information, Progenics Pharmaceuticals, Inc, July 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/ label/2018/209607s000lbl.pdf. Accessed November 8, 2018.