Vemurafenib Redifferentiation of BRAF Mutant, RAI-Refractory Thyroid Cancers

Abstract

Context: BRAFV600E mutant thyroid cancers are often refractory to radioiodine (RAI).

Objectives: To investigate the utility and molecular underpinnings of enhancing lesional iodide uptake with the BRAF inhibitor vemurafenib in patients with RAI-refractory (RAIR).

Design: This was a pilot trial that enrolled from June 2014 to January 2016.

Setting: Academic cancer center.

Patients: Patients with RAIR, BRAF mutant thyroid cancer.

Intervention: Patients underwent thyrotropin-stimulated iodine-124 (124I) positron emission tomography scans before and after ~4 weeks of vemurafenib. Those with increased RAI concentration exceeding a predefined lesional dosimetry threshold (124I responders) were treated with iodine-131 (131I). Response was evaluated with imaging and serum thyroglobulin. Three patients underwent research biopsies to evaluate the impact of vemurafenib on mitogen-activated protein kinase (MAPK) signaling and thyroid differentiation.

Main outcome measure: The proportion of patients in whom vemurafenib increased RAI incorporation to warrant 131I.

Results: Twelve BRAF mutant patients were enrolled; 10 were evaluable. Four patients were 124I responders on vemurafenib and treated with 131I, resulting in tumor regressions at 6 months. Analysis of research tumor biopsies demonstrated that vemurafenib inhibition of the MAPK pathway was associated with increased thyroid gene expression and RAI uptake. The mean pretreatment serum thyroglobulin value was higher among 124I responders than among nonresponders (30.6 vs 1.0 ng/mL; P = 0.0048).

Conclusions: Vemurafenib restores RAI uptake and efficacy in a subset of BRAF mutant RAIR patients, probably by upregulating thyroid-specific gene expression via MAPK pathway inhibition. Higher baseline thyroglobulin values among responders suggest that tumor differentiation status may be a predictor of vemurafenib benefit.

Trial registration: ClinicalTrials.gov NCT02145143.

Figure 1.

Study schema. After a baseline Thyrogen-stimulated ¹²⁴I PET scan, patients were treated with ~4 wk of vemurafenib (960 mg orally twice daily), and then re-evaluated with a second ¹²⁴I PET scan. If an index tumor met the lesional dosimetry criteria [≥2000 cGy achieved with ≤300 mCi of ¹³¹I (¹²⁴I responder)], patients were continued on vemurafenib and treated with ¹³¹I. Vemurafenib was discontinued (D/C) 2 d after ¹³¹I. Efficacy was measured with imaging at baseline, after vemurafenib alone, and ~3 mo and 6 mo after ¹³¹I. In three patients, two research biopsies were performed before treatment and then 10 to 11 d on vemurafenib.

Figure 2.

Lesional ¹²⁴I SUV_max values in patients with vemurafenib-mediated RAI enhancement. Baseline and on therapy ¹²⁴I SUV_max values among the six patients with vemurafenib-induced enhancement of tumor RAI avidity are shown. Each data point represents one tumor before and after vemurafenib therapy. ¹²⁴I responders (red) are patients 2, 6, 7, and 11; ¹²⁴I nonresponders (blue) are patients 9 and 12.

Figure 3.

Efficacy of vemurafenib alone and in combination with ¹³¹I. (a) Changes in tumor size after vemurafenib alone. Eight of the 10 evaluable study patients (four ¹²⁴I responders and four nonresponders) underwent imaging after ~4 wk of vemurafenib alone. Each bar represents the percentage change in tumor size relative to baseline observed. (b) Changes in tumor size observed among ¹²⁴I responders after vemurafenib alone and ~6 mo after ¹³¹I, relative to baseline. (c) Serum thyroglobulin values measured in ¹²⁴I responders. Serum thyroglobulins were measured at baseline, after vemurafenib alone, and 1 mo, 3 mos, and 6 mo after ¹³¹I. Patient 6 had detectable TG antibodies. (d) Outcomes of ¹²⁴I responders. Each bar represents the time each ¹²⁴I responder remained off therapy after vemurafenib plus ¹³¹I. Two patients continued to remain off therapy as of 1 November 2017. s/p, status post; Vem, vemurafenib.

Figure 4.

MAPK signaling, thyroid differentiation, and ¹²⁴I avidity. Two serial biopsies were performed on the same tumor for each patient, allowing correlation of drug-induced molecular changes with ¹²⁴I dynamics measured by PET/CT. (a) RNA was extracted from the two serial biopsies for RNAseq to quantify transcripts regulated by MAPK output, the BRS, and the eTDS. The MAPK output score, BRS, and eTDS values represent the average fold change for all mRNAs in the gene set compared with the median of all the samples. (b) Fused ¹²⁴I PET/CT images of the serially sampled tumors analyzed in (a). Gray bars indicate scores calculated in tumors obtained before vemurafenib. Black bars indicate scores calculated from biopsies obtained from the same tumors after 10 to 11 d on vemurafenib. Vem, vemurafenib.

Figure 5.

Baseline serum thyroglobulin values among the ¹²⁴I nonresponders and responders. Patient 9 (nonresponder) had a TG value of <0.1 ng/mL, which is designated here as a value of 0.1 ng/mL. Patient 6 (responder) and 9 (nonresponder) had detectable TG antibodies. Bars indicate geometric means of the values with 95% CI.