Selumetinib thwarts iodine resistance in thyroid cancer

An experimental agent known as selumetinib increased iodine uptake and retention in a subgroup of patients with thyroid cancer whose disease was resistant to radioiodine, the most effective therapy. The researchers found that selumetinib may have the most benefit for persons with RAS-mutant disease.

Metastatic thyroid cancers that are refractory to radioiodine (iodine-131) are associated with a poor prognosis, explained senior study author James A. Fagin, MD, chief of the endocrinology service at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York, New York, and colleagues in The New England Journal of Medicine. The mitogen-activated protein kinase (MAPK) pathway controls a cell's ability to absorb radioiodine; as an MAPK inhibitor, selumetinib could reverse radioiodine resistance by preventing the signaling of genetic mutations in this pathway.

After following a low-iodine diet for 5 days, 20 persons (median age 61 years) with metastatic thyroid cancer refractory to radioiodine received selumetinib. Nine of the participants had tumors with BRAF mutations and five had tumors with NRAS mutations. As noted in an MSKCC statement, NRAS is a mutation of the RAS gene, and the RAS gene is a component of the MAPK pathway.

After 4 weeks of treatment with selumetinib, all patients underwent iodine-124 positron-emission tomography (PET) to determine whether a dose of iodine-131 could be delivered to the metastatic lesions. If such uptake occurred, therapeutic radioiodine was administered while the patient was receiving selumetinib.

Selumetinib increased iodine uptake enough to allow for the administration of radioiodine therapy in eight of the patients, including all five with an NRAS mutation as well as four of the nine patients in the BRAF group. Fagin's team found that five patients had confirmed partial responses to treatment and three had stable disease. Outcomes remained unchanged during 6-month follow-up for seven of the eight patients. All eight had a reduced level of serum thyroglobulin, a blood protein used in screening for advanced thyroid cancer.

“The initial results show promise for RAS-mutant disease, but the hope is that a larger trial will shed light on whether selumetinib can be effective for a broader range of advanced thyroid cancer subtypes,” remarked Fagin in the MSKCC statement.

The investigators observed no toxic side effects of grade 3 or higher attributable to selumetinib. One patient was diagnosed with myelodysplastic syndrome more than 51 weeks after therapy, with progression to acute leukemia.

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