Enhancing Radioiodine Incorporation into Radioiodine-Refractory Thyroid Cancer with MAPK Inhibition (ERRITI): A Single-Center Prospective Two-Arm Study

Abstract

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

Patients and methods: In this prospective single-center, two-arm phase II study, patients received trametinib (BRAF-WT) or trametinib + dabrafenib (BRAF-MUT) for 21 ± 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 J statistic.

Results: Redifferentiation was achieved in 7 of 20 (35%) patients, 2 of 6 (33%) in the BRAF-MUT and 5 of 14 (36%) in the 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 2[18F]fluoro-2-deoxy-D-glucose (FDG)-PET was associated with successful redifferentiation (P = 0.01). Transient pyrexia (grade 3) and rash (grade 4) were noted in one patient each.

Conclusions: 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 thyroglobulin (Tg) decline in more than half of the treated patients. Low tumor glycolytic rate as assessed by FDG-PET is predictive of redifferentiation success. See related commentary by Cabanillas et al., p. 4164.

Figure 1.

Protocol design. QD, once daily; BID, twice daily; d/c, discontinue; WBS, whole body scintigraphy. Off-study examinations are marked with an asterisk.

Figure 2.

Efficacy of redifferentiation therapy. Treatment response of patients with successful restoration of radioiodine uptake by change in (A) Tg level, (B) RECIST summed diameter (asterisk: occurrence of new lesions), (C) PERCIST SUV_peak (asterisk: occurrence of new lesions), and (D) mean absorbed dose on a per-patient level. Waterfall plots of individual patients are sorted by best Tg response. Of note, persistence of iodine-negative lesions after redifferentiation was observed in patients 5, 6, and 7 with a consecutive increase in Tg levels at follow-up. Pre-rediff, pre-redifferentiation; post-rediff, post-redifferentiation.

Figure 3.

Association of lesion absorbed doses as assessed by ¹²⁴I PET/CT and FDG-PET. A, Box plot showing pre- and post-redifferentiation therapy lesion-based mean absorbed dose per administered ¹³¹I activity (statistical significance in Wilcoxon test indicated by an asterisk; P < 0.00001) for all patients with successful restoration of radioiodine uptake. B, Dot plot showing the per-lesion association of post-redifferentiation absorbed dose and pre-redifferentiation FDG uptake on a per-lesion level for all patients with available FDG-PET (n = 16).