Reacquisition of RAI uptake in RAI-refractory metastatic thyroid cancers by pretreatment with the MEK inhibitor selumetinib.

Abstract

5509^ Background: Therapies for radioactive iodine (RAI)-refractory thyroid cancers of follicular origin (TC-FCO) are desperately needed. TC-FCO mouse models show that blocking mitogen-activated protein kinase (MAPK) signaling with a MAP kinase kinase 1/2 (MEK1/2) inhibitor increases sodium iodide symporter expression and iodine incorporation. This 20 patient (pt) pilot study aimed to evaluate if the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142866) can reverse RAI-refractoriness in TC-FCO pts (NCT00970359). Methods: RAI-refractory TC-FCO disease was defined as: 1) non-RAI-avid lesion/s on a diagnostic or post-therapy RAI scan, 2) RAI-avid lesion/s that was stable or increased in size after RAI therapy, or 3) fluorodeoxyglucose (FDG)-avid lesion/s by positron emission tomography (PET) scan. rhTSH-stimulated lesional dosimetry with 124I PET was performed prior to and after 4 weeks of treatment with selumetinib (75 mg orally bid). If the second 124I PET scan predicted a lesional RAI dose of > 2000 cGy, therapeutic RAI was administered while on the drug. Primary endpoints were to evaluate changes in tumor iodine uptake and RECIST response after RAI therapy; changes in serum thyroglobulin (TG) after RAI was a secondary endpoint. Results: 24 pts were enrolled, 22 eligible, and 20 evaluable. For the 20 evaluable pts, median age was 61 (range 44-77 yrs), 11 were men. 19 pts had tumors analyzed for BRAF and N-,K- RAS mutations. 8 pts had BRAF mutant (MUT), 11 BRAF wild-type (WT) tumors; 1 pt to be analyzed. Selumetinib increased 124I uptake in 12 of the 20 pts (4 of 8 BRAF MUT; 8 of the 12 other pts). The 8 of those 12 pts achieving sufficient iodine avidity to warrant RAI therapy included all 5 pts known to be NRAS MUT to date and 1 BRAF MUT pt. Of the 7 pts who have received RAI, 5 had partial responses (PRs); 2 stable disease (SD). Mean percent reduction in TG in this group (pre- vs 2 months post- RAI) was 91%. No > grade 2 CTCAE toxicities attributable to selumetinib were observed. 1 pt was diagnosed with myelodysplastic syndrome > 51 weeks after RAI (unrelated to selumetinib). Conclusions: Selumetinib can enhance iodine uptake in a subset of RAI-refractory TC-FCO and may be particularly effective for RAS MUT tumors.