Results of the SEL-I-METRY Phase II Trial on Resensitization of Advanced Iodine Refractory Differentiated Thyroid Cancer to Radioiodine Therapy
Jonathan Wadsley, Gemma Ainsworth, Amy Beth Coulson, Kate Garcez, Laura Moss, Kate Newbold, Kate Farnell, Jayne Swain, Helen Howard, Matthew Beasley, Andrew Weaver, Katie Wood, J. L. Marshall, Matthew Griffin, A. Pascoe, Yong Du, J. Taprogge, Glenn Flux, Sarah Brown
Abstract
R adioactive iodine (RAI) refractory differentiated thy- roid cancer (DTC) carries a poor prognosis with a 10-year survival rate of only 10%. 1 Recently, multitargeted tyrosine kinase inhibitors have been tested in patients with RAI refractory DTC.Two phase III trials demonstrated improvements in progression-free survival (PFS): DECISION 2 showed improvement from 5.8 to 10.8 months with sorafenib, SELECT 3 demonstrated improvement from 3.6 to 18.3 months with lenvatinib.However, both agents cause significant toxicities.Treatment is continuous until disease progression, which can significantly affect quality of life.Activation of the MAP kinase signaling pathway can lead to reduced expression of the sodium iodide symporter.Selumetinib (ARRY-1428860) is an oral, potent, and highly selective allosteric MEK1/2 inhibitor that can block inappropriate signaling through this pathway and potentially restore iodine sensitivity. 4 A previously reported pilot study 5 tested selumetinib 75 mg twice daily for 4 weeks in patients with RAI refractory DTC.Of 20 patients evaluated, selumetinib increased iodine uptake (IU) in 12 patients.Of these, eight achieved sufficient uptake for further RAI, according to predefined criteria.Five of these patients had partial response and three stable disease.All had decreases in serum thyroglobulin and no grade ‡3 adverse events (AEs) were noted.SEL-I-METRY was a single-arm multicenter phase II trial, assessing whether selumetinib 75 mg twice daily for 28 days followed by 131 I therapy leads to increased PFS in patients demonstrating increased 123 I IU after selumetinib.Full trial details are reported previously. 6,7 Key eligibility criteria included measurable RAI refractory DTC that had progressed within 12 months by RECIST v1 $ 1. 8 Disease was considered RAI refractory if ‡1 measurable lesion did not demonstrate IU on a previous RAI scan, or if ‡1 measurable lesion had progressed within 12 months of RAI, despite demonstrable radioiodine avidity at the time of treatment.