Thyroid

Addition of Selumetinib to Adjuvant Radioiodine in High-Risk Differentiated Thyroid Cancer

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By Matthew Stenger

Published: 04/03/2022 11:55:00

Last update: 04/03/2022 12:32:11 PM



As reported in the Journal of Clinical Oncology by Ho et al, the phase III ASTRA trial showed no improvement in complete remission rate with the addition of selumetinib to adjuvant radioactive iodine (RAI) in patients with differentiated thyroid cancer high risk.

As the investigators stated, “Selumetinib [a MEK1/2 inhibitor] may increase RAI avidity in RAI-refractory tumors. We investigated whether selumetinib plus adjuvant RAI improves complete remission… in patients with differentiated thyroid cancer at high risk of primary treatment failure compared to RAI alone.

Study details

In the double-blind trial, 233 patients recruited from sites in eight countries between August 2013 and March 2016 were randomized 2:1 to receive selumetinib (n=155) or placebo (n = 78) in addition to the RAI. Treatment consisted of selumetinib 75 mg twice daily or placebo for approximately 5 weeks; on days 29-31 of treatment, recombinant human thyroid-stimulating hormone-stimulated RAI (0.9 mg) (131I; 100 mCi/3.7 GBq) was administered, followed by 5 days of selumetinib versus placebo.

Patients had undergone one- or two-stage total thyroidectomy with therapeutic neck dissection of clinically apparent metastatic lymph nodes and were required to have one or more high-risk pathologic features: primary tumor > 4 cm, macroscopic extrathyroidal extension (T4 disease), or metastatic or more lymph nodes measuring ≥ 1 cm or involvement of five or more lymph nodes of any size. The primary endpoint was the complete remission rate 18 months after RAI in the intention-to-treat population.

Complete remission rate

Complete remission at 18 months after AKI was achieved in 62 (40%) of 155 patients in the selumetinib group versus 30 (38%) of 78 patients in the control group (odds ratio [OR] = 1.07, 95% confidence interval [CI] = 0.61–1.87, P = .820). Among patients who received selumetinib versus placebo twice daily from 7 days before to at least 5 days after AKI (compliant population), complete remission at 18 months was achieved in 56 (47%) of patients. 120 patients in the selumetinib group versus 27 (38%) out of 72 in the control group (OR = 1.46, 95% CI = 0.81–2.67, P= .213).

  • Adding selumetinib to RAI did not improve complete remission rates.
  • No difference in response was observed according to kras state of mutation.

Of the patients for whom data are available, 125 had BRAF mutations and 17 had NRAS mutations. Complete remission at 18 months was observed in: 34 (37%) of 91 patients versus 21 (41%) of 25 patients with mutant BRAF Where NRAS (OR=0.85, 95% CI=0.42–1.73, P = 0.655); 30 (36%) of 84 versus 15 (37%) of 41 with mutant BRAF (OR=0.96, 95% CI=0.45–2.12, P = 0.924); and 24 (44%) of 54 versus 10 (38%) of 26 with wild type BRAF (OR=1.28, 95% CI=0.50–3.40, P = 0.611).

No significant differences in complete remission rates between groups were observed in the analysis by histology, age, sex or ethnicity.

Adverse events

The most common adverse events of all grades in the selumetinib group were acneiform dermatitis (45%) and diarrhea (44%). Grade ≥ 3 adverse events occurred in 18% of patients in the selumetinib group vs. 1% in the control group (treatment-related in 16% vs. 0%); the most common in the selumetinib group were acneiform dermatitis (7%) and increased creatine phosphokinase (3%).

Serious treatment-related adverse events occurred in four patients in the selumetinib group (acneiform dermatitis in two, drug hypersensitivity in one and gastric bleeding in one). Adverse events led to discontinuation of treatment in 18 patients (12%) vs 0 patient, most commonly due to acneiform dermatitis in seven patients (5%); four other patients discontinued selumetinib due to ophthalmologic adverse events. No treatment-related deaths were reported.

The researchers concluded: “Postoperative disease risk stratification identified patients with differentiated thyroid cancer at high risk of primary treatment failure, although adding selumetinib to adjuvant RAI did not improve the rate of complete remission in these patients Future strategies should focus on selecting drugs appropriate to the tumor genotype and maintaining drug dosing to optimize the efficacy of RAI.

Alan L. Ho, MD, PhDof Memorial Sloan Kettering Cancer Centeris the corresponding author for the Journal of Clinical Oncology item.

Disclosure: The study was funded by grants from the National Cancer Institute and by AstraZeneca. For full disclosures from the study authors, visit ascopubs.org.

The content of this article has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the views and opinions of ASCO®.