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 high-risk differentiated thyroid cancer.
As stated by the investigators, “Selumetinib [a MEK1/2 inhibitor] can 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 vs RAI alone.”
Study Details
In the double-blind trial, 233 patients enrolled from sites in eight countries between August 2013 and March 2016 were randomly assigned 2:1 to receive selumetinib (n = 155) or placebo (n = 78) along with RAI. Treatment consisted of selumetinib at 75 mg twice daily or placebo for approximately 5 weeks; on treatment days 29 to 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 vs placebo.
Patients had undergone one- or two-stage total thyroidectomy with therapeutic neck dissection of clinically apparent metastatic lymph nodes and had to have one or more high-risk pathologic features: primary tumor > 4 cm, gross extrathyroidal extension (T4 disease), or one or more metastatic lymph nodes measuring ≥ 1 cm or involvement of five or more lymph nodes of any size. The primary endpoint was complete remission rate 18 months after RAI in the intention-to-treat population.
Complete Remission Rates
Complete remission at 18 months after RAI was achieved in 62 (40%) of 155 patients in the selumetinib group vs 30 (38%) of 78 in the control group (odds ratio [OR] = 1.07, 95% confidence interval [CI] = 0.61–1.87, P = .820). Among patients who received selumetinib vs placebo twice daily from 7 days before to 5 days after RAI at a minimum (treatment-compliant population), complete remission at 18 months was achieved in 56 (47%) of 120 in the selumetinib group vs 27 (38%) of 72 in the control group (OR = 1.46, 95% CI = 0.81–2.67, P = .213).
KEY POINTS
- The addition of selumetinib to RAI did not improve rates of complete remission.
- No differences in response were observed according to KRAS mutation status.
Among patients with available data, 125 had BRAF mutations and 17 had NRAS mutations. Complete remission at 18 months was observed in: 34 (37%) of 91 patients vs 21 (41%) of 25 patients with mutant BRAF or NRAS (OR = 0.85, 95% CI = 0.42–1.73, P = .655); 30 (36%) of 84 vs 15 (37%) of 41 with mutant BRAF (OR = 0.96, 95% CI = 0.45–2.12, P = .924); and 24 (44%) of 54 vs 10 (38%) of 26 with wild-type BRAF (OR = 1.28, 95% CI = 0.50–3.40, P = .611).
No significant differences in complete remission rates between groups were observed in analysis according to histology, age, sex, or ethnicity.
Adverse Events
The most common adverse events of any grade 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% of 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%).
Treatment-related serious adverse events occurred in four patients in the selumetinib group (acneiform dermatitis in two, drug hypersensitivity in one, and gastric hemorrhage in one). Adverse events led to treatment discontinuation in 18 patients (12%) vs 0 patients, most commonly due to acneiform dermatitis in seven patients (5%); an additional four patients discontinued selumetinib due to ophthalmologic adverse events. No treatment-related deaths were reported.
The investigators concluded, “Postoperative pathologic risk stratification identified patients with differentiated thyroid cancer at high risk of primary treatment failure, although the addition of selumetinib to adjuvant RAI failed to improve the complete remission rate for these patients. Future strategies should focus on tumor genotype–tailored drug selection and maintaining drug dosing to optimize RAI efficacy.”
Alan L. Ho, MD, PhD, of Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by grants from the National Cancer Institute and by AstraZeneca. For full disclosures of the study authors, visit ascopubs.org.
