Re-differentiation of radioiodine-refractory BRAF V600E-mutant thyroid carcinoma with dabrafenib: A pilot study.

Abstract

6025 Background: Resistance to radioactive iodine is a leading cause of mortality in differentiated thyroid carcinoma. The MAPK pathway is a major determinant of iodine uptake into thyroid carcinoma cells. Mutations in BRAF activate this pathway, resulting in resistance to radioactive iodine. A pilot study using the MEK1/2 inhibitor, selumetinib, (Ho, ASCO 2012) increased radioiodine uptake in a subset of thyroid cancers. Methods: This is a single institution, single arm pilot study investigating the potential for the BRAF inhibitor dabrafenib to induce radioiodine uptake in metastatic, BRAF-mutant, radioiodine-refractory papillary thyroid carcinoma (PTC). The primary endpoint is increased radioiodine uptake demonstrated on a 4mCi 131-I whole body scan. Patients with increased uptake receive 14 additional days of dabrafenib followed by treatment with 150mCi 131-I. Secondary endpoints include safety and tolerability and clinical benefit as measured by decreases in serum thyroglobulin and objective response rate per modified RESIST 1.1. Results: To date, 7 patients have been enrolled. All had negative 131-I scans within 14 months of enrollment. No dose adjustments for toxicity have been needed. One patient developed reversible hypophosphatemia and a second developed a benign skin lesion. 3 of 5 evaluable patients developed radioiodine uptake after 28 days of dabrafenib, and new radioiodine-avid lesions were demonstrated in all three after receiving a therapeutic dose of 131-I. All three patients demonstrated increases in thyroglobulin levels during treatment with dabrafenib. Conclusions: This initial data suggests that a subset of patients with radioiodine-resistant BRAF-mutant PTC demonstrate new iodine uptake following treatment with dabrafenib. Reuptake may correlate with increases in thyroglobulin, suggestive of re-differentiation. It is not yet known whether increased uptake of radioactive iodine will translate into a radiographic response. Two patients failed to convert to radioiodine-sensitive disease; it is possible that BRAF inhibition was incomplete in these patients and/or determinants other than BRAF mutation status contribute to radioiodine sensitivity. Clinical trial information: NCT01534897.