Abstract and Introduction
Purpose: Selumetinib can increase radioactive iodine (RAI) avidity in RAI-refractory tumors. We investigated whether selumetinib plus adjuvant RAI improves complete remission (CR) rates in patients with differentiated thyroid cancer (DTC) at high risk of primary treatment failure versus RAI alone.
Methods: ASTRA (ClinicalTrials.gov identifier: NCT01843062) is an international, phase III, randomized, placebo-controlled, double-blind trial. Patients with DTC at high risk of primary treatment failure (primary tumor > 4 cm; gross extrathyroidal extension outside the thyroid gland [T4 disease]; or N1a/N1b disease with ≥ 1 metastatic lymph node(s) ≥ 1 cm or ≥ 5 lymph nodes [any size]) were randomly assigned 2:1 to selumetinib 75 mg orally twice daily or placebo for approximately 5 weeks (no stratification). On treatment days 29–31, recombinant human thyroid-stimulating hormone (0.9 mg)–stimulated RAI (131I; 100 mCi/3.7 GBq) was administered, followed by 5 days of selumetinib/placebo. The primary end point (CR rate 18 months after RAI) was assessed in the intention-to-treat population.
Results: Four hundred patients were enrolled (August 27, 2013-March 23, 2016) and 233 randomly assigned (selumetinib, n = 155 [67%]; placebo, n = 78 [33%]). No statistically significant difference in CR rate 18 months after RAI was observed (selumetinib n = 62 [40%]; placebo n = 30 [38%]; odds ratio 1.07 [95% CI, 0.61 to 1.87]; P = .8205). Treatment-related grade ≥ 3 adverse events were reported in 25/154 patients (16%) with selumetinib and none with placebo. The most common adverse event with selumetinib was dermatitis acneiform (n = 11 [7%]). No treatment-related deaths were reported.
Conclusion: Postoperative pathologic risk stratification identified patients with DTC at high risk of primary treatment failure, although the addition of selumetinib to adjuvant RAI failed to improve the CR rate for these patients. Future strategies should focus on tumor genotype–tailored drug selection and maintaining drug dosing to optimize RAI efficacy.
Thyroid surgery followed by radioactive iodine (RAI) is standard management for patients with differentiated thyroid cancer (DTC) at high and intermediate risk of disease persistence or recurrence. In the adjuvant setting, RAI is administered to consolidate complete remission (CR), although prospective trials verifying benefit have not been performed. Successful initial therapy is crucial because most patients with DTC who achieve remission do not experience recurrence (approximately 1%–4% over median follow-up periods of 5–10 years).[2–4]
Retrospective studies have identified primary tumor size/extent of invasion (> 4 cm or gross extrathyroidal extension outside the thyroid gland [T4 disease]) and lymph node status (N1a/N1b disease with ≥ 1 metastatic lymph node ≥ 1 cm or ≥ 5 lymph nodes of any size) as predictive for a high risk for failing initial therapy (unpublished analysis on the basis of studies by Tuttle et al and Vaisman et al). Approximately 70% of patients whose disease met any one of these criteria failed to achieve CR with surgery and RAI, requiring more intensive surveillance, tests/evaluations, and therapies. Novel approaches to enhance RAI activity could improve outcomes for these patients.
Up to approximately 70% of DTCs harbor mutations that activate the RAS/RAF/MEK/ERK (RAS-ERK) pathway,[5–9] which represses gene expression required for iodine avidity to mediate RAI-refractoriness.[10,11] In mouse models of BRAF-mutant thyroid cancer, ablation of BRAF activation restored iodine avidity. Selumetinib is a potent and highly selective allosteric MEK 1/2 inhibitor (AZD6244, ARRY-142886)[13–15] with a short half-life. A pilot clinical trial demonstrated that selumetinib increased iodine avidity and efficacy in 8/20 patients with recurrent/metastatic RAI-refractory thyroid cancer.
To test the hypothesis that selumetinib enhances RAI efficacy in the adjuvant setting, we conducted the phase III Adjuvant Selumetinib for differentiated Thyroid cancer, Remission after RAI (ASTRA) trial to compare the CR rate achieved with adjuvant RAI in combination with placebo versus selumetinib in patients with DTC at high risk of primary treatment failure.
J Clin Oncol. 2022;40(17):1870-1878. © 2022 American Society of Clinical Oncology