Letter to the Editor: Selpercatinib-Enhanced Radioiodine Uptake in RET-Rearranged Thyroid Cancer

Dear Editor:

Differentiated thyroid cancers have worse prognosis if the metastatic tissue is radioactive iodine (RAI)-refractory or loses the ability to take up iodine-131 (¹³¹I). Activating mutations of oncogenes or rearrangement resulting in fusion genes have been identified as driver events underlying the dedifferentiation process. The possibility of restoring RAI uptake in tumors harboring BRAF or RAS mutations was demonstrated with Mitogen-Activated Protein Kinase pathway inhibitors (BRAF and MEK inhibitors) (1,2). A recent and unique observation of RAI reuptake under larotrectinib suggested the possibility to extend this concept to fusion genes (3). Similar findings with another fusion gene would reinforce the proof of concept of this new therapeutic opportunity.

We report the therapeutic sequence of a 73-year-old female patient diagnosed at the age of 15 with papillary thyroid cancer. A late recurrence 44 years after the initial thyroidectomy required cervical lymph node dissection, followed by five RAI treatments (cumulative dose of 18.5 GBq [500 mCi]) due to miliary lung metastases. Five years after the last ¹³¹I therapy, pulmonary metastasectomy and ribs resection were performed due to limited disease progression. A year later, progression of bone and thoracic metastases required systemic treatment. Molecular screening identified only a fusion gene (NCOA4-RET), and treatment with the new selective RET inhibitor selpercatinib was initiated (4). Diagnostic scintigraphy performed before selpercatinib confirmed RAI refractory disease (Fig. 1). A new diagnostic RAI scintigraphy performed 3 weeks after the initiation of selpercatinib (160 mg twice daily) showed restoration of RAI uptake. A therapeutic RAI dose was administered 2 weeks later and redifferentiation was confirmed on post-therapy scan with RAI uptake in all fluorine 18 fluorodeoxyglucose (18F-FDG) avid lesions. Given the high volume of the disease, selpercatinib was continued after RAI therapy. The evaluation 6 months after RAI therapy showed partial metabolic response on positron emission tomography 18F-FDG (there was no target lesion according to response evaluation criteria in solid tumors [RECIST] on computed tomography). Suppressed thyroglobulin at 6 months was 441 μg/mL versus 253 at baseline, which could be explained by a redifferentiation effect of the treatment.

OPEN IN VIEWER

FIG. 1.

Post-iodine 131 scans obtained before and after selpercatinib treatment. (A, B) Diagnostic scans were obtained with the use of iodine 131 (295 MBq [8 mCi]) before treatment with selpercatinib and 3 weeks after the initiation of treatment. At baseline, anterior image of the whole-body scan shows no iodine uptake in metastases with only physiological gastrointestinal tract elimination. After selpercatinib, the whole-body scan shows restored iodine uptake in almost all metastases that had previously shown no uptake, including bone metastases. (C) Additional metastatic foci of iodine uptake (three arrows) can be observed on the post-therapeutic (3700 MBq [100 mCi]) scan after 5 weeks of selpercatinib treatment.

This finding of a redifferentiation effect with selpercatinib targeting a RET fusion gene reinforces the proof of concept of this new therapeutic opportunity. Therefore, future clinical trials and treatment strategies should evaluate the redifferentiating effect of drugs targeting gene rearrangements. Furthermore, the combined approach with a targeted therapy and RAI may increase antitumor efficacy and minimize acquired resistance to RET inhibitors (5).