Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer

Abstract

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.).

Figure 1. Protocol Design and Changes in Iodine Uptake

Panel A shows the protocol design. Baseline iodine avidity in the lesion was first assessed with thyrotropin alfa–stimulated iodine-124 positron-emission tomographic–computed tomographic (PET-CT) scanning. Patients were then treated with selumetinib at a dose of 75 mg given orally twice a day for 4 weeks. In the final week of treatment, a second thyrotropin alfa–stimulated ¹²⁴I PET-CT study was performed. The double arrows indicate the two thyrotropin alfa injections. Patients with ¹²⁴I dosimetry that predicted tumor uptake of less than 2000 cGy discontinued the study. If the absorbed dose of radioiodine in the lesion was predicted to be 2000 cGy or greater, full dosimetry with iodine-131 was performed to calculate the maximum tolerable activity that could be administered safely. Patients then received a therapeutic dose of radioiodine the next week after preparation with thyrotropin alfa. Selumetinib was continued until 2 days after the administration of therapeutic radioiodine. Thyroglobulin levels and the radiographic response were assessed at 2 and 6 months after radioiodine administration. Panel B shows a summary of the changes in iodine uptake quantified by ¹²⁴I PET-CT and the number of patients who met the criteria for treatment with iodine-131.

Figure 2. Iodine-124 PET-CT Scans Obtained before and after Selumetinib Treatment in Selected Patients with Positive Responses

Panel A shows whole-body maximum-intensity projection images of a patient with a BRAF-mutant papillary thyroid cancer. New iodine uptake is shown in nearly all previously negative lung and neck metastases. Panel B shows fused axial PET-CT images of a patient with an NRAS-mutant, poorly differentiated thyroid cancer. Both new and significantly increased iodine uptake in lung metastases is shown. Panels C and D show PET-CT images from another patient with an NRAS-mutant, poorly differentiated thyroid cancer. In Panel C, fused axial PET-CT images show significantly increased iodine uptake in a sacroiliac bone metastasis after administration of selumetinib (right). In Panel D, fused axial images (top and bottom left) show new iodine uptake in a previously negative site as well as increased avidity in a large left parietal skull metastasis. Three-dimensional rendering highlights changes in the left parietal skull metastasis before and after selumetinib (top and bottom right).

Figure 3. Quantification of Iodine-124 PET Uptake in a Lesion in a Patient with an NRAS Mutation Who Later Received Radioiodine

Panel A shows the maximal standardized uptake value (SUV_max) for iodine in all tumors in a patient with an NRAS-mutant, poorly differentiated thyroid cancer. Each bar represents one malignant lesion identified on the iodine-124 PET-CT scan. The bars to the left indicate the increases in iodine-124 avidity achieved after selumetinib administration in lesions that absorbed some iodine at baseline. The bars on the right indicate selumetinib-induced changes in lesions that were negative for iodine at baseline. Panel B shows the SUV_max in every metastatic lesion identified in the same patient before and after the administration of selumetinib. The dashed lines mark points on the graph corresponding to different degrees of change in the SUV_max in the lesion after the administration of selumetinib. The red dashed line demarcates no change in iodine uptake after the administration of selumetinib (0%). Dashed lines to the left of the red dashed line represent graded percentage increases in iodine-124 uptake (+25%, +50%, and +100%), whereas the lines to the right represent graded percentage decreases (−25%, −50%, and −75%). Nearly all the metastatic lesions in this patient (circles) had more than a 100% increase in iodine uptake after administration of selumetinib. The SUV_max for a sternal metastasis was off the scale (it increased from 220 to 599 with selumetinib) and thus could not be included in these graphs without obscuring the data for the other 54 lesions analyzed.

Figure 4. Response to Iodine-131 Therapy with Selumetinib Treatment

Panel A shows a waterfall plot of the maximum change in target lesions (relative to a prestudy scan) in the eight patients who received therapeutic radioiodine. The best overall response in each patient according to the Response Evaluation Criteria in Solid Tumors, version 1.1, is also shown. The dashed line indicates a 30% reduction in tumor dimensions. WT denotes wild-type. Panel B shows serum thyroglobulin values in the eight patients treated with radioiodine. NA denotes not available.