Dabrafenib May Stimulate Radioiodine Uptake in Patients With Iodine-Refractory Papillary Thyroid Cancer
In patients with iodine-refractory papillary thyroid cancer, the addition of dabrafenib (Tafinlar) therapy was shown to stimulate radioiodine uptake in thyroid cancer cells, according to a report by Rothenberg et al in Clinical Cancer Research. This approach has the potential advantage of requiring only a short course of minimally toxic targeted therapy to maximize the potential long-term therapeutic effect of radioiodine therapy.
Oncologists are well aware that radioactive iodine is a highly specific and effective treatment for patients with differentiated unresectable or metastatic thyroid cancer. Unfortunately, many patients on radioactive iodine become refractory to the treatment over time. One investigational approach to overcome this refractoriness in these patients is to administer a short course of the BRAF inhibitor dabrafenib.
To further attempt to determine the feasibility of dabrafenib in this patient population, Rothenberg and colleagues conducted a study to determine whether dabrafenib was capable of stimulating radioiodine uptake in BRAF V600E–mutated unresectable or metastatic iodine-refractory papillary thyroid cancer. Tumors harboring BRAF mutations are generally more aggressive and may lead to radioiodine insensitivity and possible death.
Study Details
Included in the study were 10 patients with BRAF V600E–mutant iodine-refractory papillary thyroid cancer. Each patient received dabrafenib (150 mg twice daily) for 25 days prior to thyrotropin alfa–stimulated iodine-131 whole-body scan. Patients whose scan showed new evidence of radioiodine uptake continued to receive dabrafenib for 17 more days and then were treated with 150 mCi (5.5 GBq) of iodine-131. Patients continued to receive their levothyroxine-suppressive therapy throughout the study.
The primary endpoint of the study was the percentage of patients with new radioiodine uptake after treatment with dabrafenib. This would be correlative to tumor response. Secondary endpoints included best tumor response after radioiodine treatment according to RECIST 1.1 and change in serum thyroglobulin concentration from baseline to 3 months after radioiodine treatment.
New Radioiodine Uptake Seen in the Majority of Patients
While receiving dabrafenib therapy, 60% of the patients developed new radioiodine uptake. Three of four patients with fluorodeoxyglucose-positive disease and one patient with fluorodeoxyglucose-negative disease developed new radioiodine uptake while receiving dabrafenib therapy. New radioiodine uptake was found in four of five patients with documented progressive disease.
Six months after renewed treatment with radioiodine, there was a reduction in the size of target lesions on computed tomography (CT) imaging in five of the six treated patients. Of the four patients with stable disease who were treated with radioactive iodine, three demonstrated a reduction in the size of the target lesions (by 12%–20%), and one had a slight increase (3%). Although thyroid-stimulating hormone–suppressed thyroglobulin concentrations decreased in four of six patients with new radioactive iodine uptake at 3 months, the differences were not statistically significant.
As for safety, all patients completed the full course of dabrafenib without dose modification. Adverse events occurring in more than a single patient included new skin lesions or changes (80%), fatigue (50%), gastrointestinal symptoms (50%), electrolyte abnormalities (50%), palmar-plantar erythrodysesthesia (40%), headache (30%), nausea (20%), weight loss (20%), creatinine increase (20%), and epistaxis (20%). All of these adverse events resolved upon completion of the study.
Closing Thoughts
According to the investigators, BRAF inhibition can induce radioiodine uptake in BRAF V600E–mutant iodine-refractory patients with papillary thyroid cancer. For patients with advanced thyroid cancer, this approach has the potential advantage of requiring only a short course of minimally toxic targeted therapy to maximize the potential long-term therapeutic effect of radioiodine therapy.
“Our results with the selective BRAF inhibitor dabrafenib provide additional support for the hypothesis that MAPK pathway inhibition can restore sensitivity to radioiodine by facilitating redifferentiation of iodine-refractory advanced thyroid cancer,” they concluded.
Lori J. Wirth, MD, of the Center for Head and Neck Cancers, Massachusetts General Hospital, Boston, is the corresponding author of this article in Clinical Cancer Research.
Research for this study was supported in part by GlaxoSmithKline and a grant from the Ellison Foundation. The authors reported no potential conflicts of interest.
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