Selumetinib and RAI Fails to Achieve Significant CR in Differentiated Thyroid Cancer

While clinicians were able to identify patients with differentiated thyroid cancer (DTC) at high risk of primary treatment failure through postoperative pathologic risk stratification, the addition of selumetinib (Koselugo) to adjuvant radioactive iodine (RAI) did not improve complete remission [CR] rates, according to data from the ASTRA (NCT01843062) trial.¹

Data from the international phase 3, randomized, placebo-controlled, double blind trial showed that the use of pathologic criteria to conduct risk stratification can accurately identify patients that standard treatment won’t be curative. The study was conducted based on previous retrospective analyses and researchers, writing in the Journal of Clinical Oncology, predicted a 30% CR rate in patients with DTC based on this as well as the high-risk pathologic criteria found in the trial. What they found was that 38% of patients in the RAI plus placebo arm achieved CR, which suggests the high-risk disease criteria successfully identified a group of patients that showed standard surgery and RAI was insufficient for curative goals.

Patients with DTC at high risk of primary treatment failure were defined by having a primary tumor larger than 4 cm; gross extrathyroidal extension outside the thyroid gland, known as T4 disease; or N1a/N1b disease with 1 or more metastatic lymph nodes 1 cm or larger, and lymph nodes of any size 5 cm or greater. These patients were then assigned 2:1 to 75 mg selumetinib (n = 155) given orally twice daily or placebo (n = 78) for 5 weeks, with no stratification. Then on treatment days 29-31, 0.9 mg of recombinant human thyroid-stimulating hormone–stimulated RAI (131I; 100 mCi/3.7 GBq) was given followed by another 5 days of selumetininb or placebo.

The primary endpoint of the study was CR rates after 18 months of RAI treatment, which researchers found no significant improvement for patients receiving selumetinib plus RAI (n = 62) vs patients on placebo plus RAI (n = 30) with an odds ratio (OR) of 1.07 (95% CI, 0.61-1.87; P = .8205).

While there was a larger number of patients on the treatment arm who experienced CR compared with the placebo arm, researchers noted that when restricting the analysis to the treatment-compliant analysis set there still was not a significant difference between either arm, with 56 patients (47%) and 27 patients (38%) having CR in the selumetinib and placebo arms, respectively (OR, 1.46; 95% CI, 0.81-2.67; P = .2131). Moreover, a prespecified sensitivity analysis of the primary endpoint found no significant difference between CR in either arm when using logistic regression analysis that was adjusted for mutation status, histology, and age.

However, all patients who met 18-month clinical remission criteria, defiend as negative rhTSH-stimulated thyroglobulin/diagnostic whole-body scan and neck ultrasound, met the primary CR criteria, that required further negative MRI neck and CT chest scans, which continued to suggest to researchers that standard clinical surveillance is sufficient for detecting persistent or recurrent disease.

“The reason for the lack of benefit observed with selumetinib in ASTRA may be informed by recent work identifying factors requisite for successful redifferentiation, (such as), sustained and potent MAPK inhibition essential for successful restoration of the thyroid-specific gene expression required for RAI avidity,” the researchers wrote. “Given that the MAPK pathway inhibition and differentiation status are readily reversible phenomena in our preclinical studies, we reasoned that missed or inconsistent drug dosing could result in loss of the redifferentiation effects achieved.”

Overall, 205 patients had a positive or known BRAF genomic status and 203 patients also had a known RAS mutation status. In a subgroup analysis of these patients both patients with a BRAF (n = 125) or NRAS (n = 17) mutation there was no significant difference in the complete or clinical remission rates at 18 months for patients on selumetinib (37%) vs those on placebo (41%) (OR, 0.85; 95% CI, 0.42-1.73, P = .6549). Moreover, no significant difference was found in patients with mutant BRAF disease at 36% of patients on selumetinib and 37% with placebo (OR, 0.96; 95% CI, 0.45-2.12, P = .9242) or wild-type BRAF mutations, at 44% with selumetinib and 38% with placebo (OR, 1.28; 95% CI, 0.50-3.40, P = .6112). Further subgroup analyses showed no other significant differences of the CR rate when patients were categorized by histology, age, sex, or ethnicity.

“The increased absolute difference in the 18-month CR rate in favor of selumetinib for the treatment-compliant set is consistent with the hypothesis that uninterrupted treatment during this period may be important,” the researchers added. “More work is needed to definitively determine the duration and critical period of therapy necessary to optimize redifferentiation.”

When compared with placebo there were more adverse events (AEs) observed on patients with selumetinib at 98% (n = 151) and 75% (n = 58) for those on placebo. Most AEs were grade 1 or 2, but grade 3 AEs were reported in 18% of patients on selumetinib and 1% of patients on placebo, with treatment-related AEs reflecting this split with 16% of patients in the treartment arm experiencing these vs 0% in the placebo arm. The most frequent grade 3 AEs were dermatitis acneiform (45%) and increased blood creatine phosphokinase (7%), with 44% of patients experiencing diarrhea. Serious AEs were seen in 4 patients and determined to be related to selumetinib with dermatitis acneiform (n = 2), drug hypersensitivity (n = 1), and gastric hemorrhage (n = 1). One patient was permanently discontinued from selumetinib due to a serious AE of skin rash and another patient’s selumetinib was interrupted and reduced to 100 mg due to their rash.

“Future efforts to enhance RAI efficacy must focus on tailoring the pharmacologic approach to tumor genotype and improving treatment tolerability/compliance to optimize clinical efficacy,” the researchers concluded.

_Reference

_{Ho AL, Dedecjus M, Wirth LJ, ASTRA investigator group, et al. Selumetinib Plus Adjuvant Radioactive Iodine in Patients With High-Risk Differentiated Thyroid Cancer: A Phase III, Randomized, Placebo-Controlled Trial (ASTRA). J Clin Oncol. 2022 Jun 10;40(17):1870-1878. doi: 10.1200/JCO.21.00714}