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Enhancing Radioiodine Incorporation Into Radio Iodine Refractory Thyroid Cancer With MAPK Inhibition (ERRITI): A Single-Center Prospective Two-Arm Study

Purpose: Restoration of iodine incorporation (redifferentiation) by mitogen-activated protein kinase (MAPK) inhibition was achieved in previously radioiodine-refractory, unresectable thyroid carcinoma (RR-TC). However, results were unsatisfactory in BRAFV600E-mutant RR-TC. Here we assess safety and efficacy of redifferentiation therapy through genotype-guided MAPK-modulation in patients with BRAFV600E-mutant (BRAF-MUT) or wildtype (BRAF-WT) RR-TC.

Experimental design: In this prospective single-center two-arm phase-II study, patients received trametinib (BRAF-WT) or trametinib+dabrafenib (BRAF-MUT) for 21{plus minus}3 days. Redifferentiation was assessed by 123I-scintigraphy. In case of restored radioiodine uptake, 124I-guided 131I therapy was performed. Primary endpoint was the redifferentiation rate. Secondary endpoints were treatment response (thyroglobulin, RECIST 1.1) and safety. Parameters predicting successful redifferentiation were assessed using a receiver operating characteristic analysis and Youden's J statistic.

Results: Redifferentiation was achieved in 7/20 (35%) patients, 2/6 (33%) in BRAF-MUT and 5/14 (36%) in BRAF-WT arm. Patients received a mean (range) activity of 300.0 (273.0-421.6) mCi for 131I therapy. Any thyroglobulin decline was seen in 57% (4/7) of the patients, RECIST 1.1 stable/partial response/progressive disease in 71% (5/7) / 14% (1/7) / 14% (1/7). Peak standardized uptake value (SUVpeak) <10 on FDG-PET was associated with successful redifferentiation (p=0.01). Transient pyrexia (grade 3) and rash (grade 4) were noted in one patient each.

Conclusion: Genotype-guided MAPK inhibition was safe and resulted in successful redifferentiation in about one third of patients in each arm. Subsequent 131I therapy led to a Tg decline in more than half of the treated patients. Low tumor glycolytic rate as assessed by FDG-PET is predictive of redifferentiation success.

Related Products

Cat.No. Product Name Information
S2673 Trametinib (GSK1120212) Trametinib (GSK1120212, JTP-74057) is a highly specific and potent MEK1/2 inhibitor with IC50 of 0.92 nM/1.8 nM in cell-free assays, no inhibition of the kinase activities of c-Raf, B-Raf, ERK1/2. Trametinib activates autophagy and induces apoptosis.

Related Targets

Apoptosis related MEK Autophagy