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Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer
Alan L Ho1, Ravinder K Grewal, Rebecca Leboeuf
1Head and Neck Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY 10065, USA.
Background:
Metastatic thyroid cancers that are refractory to radioiodine (iodine-131) are associated with a poor prognosis. In mouse models of thyroid cancer, selective mitogen-activated protein kinase (MAPK) pathway antagonists increase the expression of the sodium-iodide symporter and uptake of iodine. Their effects in humans are not known.
Methods:
We conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer. After stimulation with thyrotropin alfa, dosimetry with iodine-124 positron-emission tomography (PET) was performed before and 4 weeks after treatment with selumetinib (75 mg twice daily). If the second iodine-124 PET study indicated that a dose of iodine-131 of 2000 cGy or more could be delivered to the metastatic lesion or lesions, therapeutic radioiodine was administered while the patient was receiving selumetinib.
Results:
Of 24 patients screened for the study, 20 could be evaluated. The median age was 61 years (range, 44 to 77), and 11 patients were men. Nine patients had tumors with BRAF mutations, and 5 patients had tumors with mutations of NRAS. Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients (4 of 9 patients with BRAF mutations and 5 of 5 patients with NRAS mutations). Eight of these 12 patients reached the dosimetry threshold for radioiodine therapy, including all 5 patients with NRAS mutations. Of the 8 patients treated with radioiodine, 5 had confirmed partial responses and 3 had stable disease; all patients had decreases in serum thyroglobulin levels (mean reduction, 89%). No toxic effects of grade 3 or higher attributable by the investigators to selumetinib were observed. One patient received a diagnosis of myelodysplastic syndrome more than 51 weeks after radioiodine treatment, with progression to acute leukemia.
Conclusions:
Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. (Funded by the American Thyroid Association and others; ClinicalTrials.gov number, NCT00970359.).
Insights
Selumetinib, a MEK inhibitor, can re-sensitize radioiodine-refractory thyroid cancer to treatment by increasing iodine uptake. This approach shows promise, particularly for patients with RAS-mutant tumors.
Area of Science:
- Oncology
- Molecular Biology
- Radiopharmaceuticals
Background:
- Metastatic thyroid cancer refractory to radioiodine (iodine-131) has a poor prognosis.
- Mitogen-activated protein kinase (MAPK) pathway antagonists in mouse models increase sodium-iodide symporter expression and iodine uptake.
- The effects of MAPK pathway antagonists in human thyroid cancer are unknown.
Purpose of the Study:
- To determine if selumetinib (a MEK 1 and MEK 2 inhibitor) can reverse radioiodine refractoriness in metastatic thyroid cancer patients.
- To assess the impact of selumetinib on iodine uptake and its potential to enable radioiodine therapy.
Main Methods:
- A study involving 20 evaluable patients with metastatic thyroid cancer.
- Patients received selumetinib (75 mg twice daily) after thyrotropin alfa stimulation.
- Dosimetry with iodine-124 positron-emission tomography (PET) was performed before and after selumetinib treatment to assess iodine uptake.
Main Results:
- Selumetinib increased iodine-124 uptake in 12 of 20 patients (60%), including all 5 with NRAS mutations.
- Eight patients met the dosimetry threshold for radioiodine therapy, with 5 achieving partial responses and 3 stable disease.
- All treated patients showed significant decreases in serum thyroglobulin levels (mean reduction, 89%).
Conclusions:
- Selumetinib significantly increases iodine uptake and retention in a subset of radioiodine-refractory thyroid cancer patients.
- The effectiveness of selumetinib may be more pronounced in patients with RAS-mutant thyroid cancer.
- This approach offers a potential strategy to re-sensitize thyroid cancer to radioiodine therapy.
