Mitogen-Activated Protein Kinase Pathway Inhibition for Redifferentiation of Radioiodine Refractory Differentiated Thyroid Cancer: An Evolving Protocol

Background: Some patients with metastatic differentiated thyroid cancer (DTC) lack iodine avidity and are therefore unsuitable for radioactive iodine (RAI) therapy. Limited experience suggests that single-agent selective mitogen-activated protein kinase (MAPK) pathway inhibitors can restore expression of the sodium–iodide symporter rendering RAI refractory (RAIR) DTC patients amenable to RAI therapy. The aim of this study was to assess the feasibility of mutation-guided MAPK-pathway blockade combined with thyroid hormone withdrawal (THW) for redifferentiation. Methods: This is a retrospective review of metastatic RAIR DTC and driver mutation in MAPK pathway, treated on a redifferentiation protocol. All patients had metastatic disease that had never been RAI-avid and/or imaging and biochemical progression despite treatment with RAI within the past 12 months. Patients with tumors harboring an NRAS mutation were treated with an MEK inhibitor (trametinib), and tumors with a BRAF V600E mutation with combined BRAF and MEK inhibition (dabrafenib and trametinib; or vemurafenib and cobimetinib) for four weeks. Thyrotropin stimulation was performed by THW for four weeks. Restoration of RAI uptake was determined by 124 I positron emission tomography/computed tomography imaging. The response was assessed at least three months post-RAI. Results: From 2015 to 2017, six patients (age 45–70, four females) received redifferentiation therapy. Three patients had an NRAS mutation; two with follicular thyroid carcinoma (FTC) and one with a poorly differentiated thyroid carcinoma (PDTC); and three patients had a BRAF V600E mutation and papillary thyroid carcinoma (PTC). One NRAS and all BRAF V600E mutation cases demonstrated restoration of RAI uptake and proceeded to RAI therapy with a median follow-up of 16.6 months (range 13.5–42.3 months). The patient with an NRAS mutation and two of three patients with a BRAF V600E demonstrated partial imaging response beyond a three-month follow-up. Grade 3 adverse events (acneiform rash) were observed in two patients with NRAS mutations. Conclusions: Mutation-guided MAPK pathway inhibition with MEK inhibitor or a combination of BRAF inhibitor and MEK inhibitor under concurrent THW is a feasible and a promising strategy to redifferentiate RAIR DTC, thereby rendering them suitable for RAI therapy with satisfactory retention following treatment.