Selumetinib Plus Adjuvant Radioactive Iodine in Patients With High-Risk Differentiated Thyroid Cancer: A Phase III, Randomized, Placebo-Controlled Trial (ASTRA).

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 ( ¹³¹ I; 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.
Competing Interests: Alan L. HoConsulting or Advisory Role: Bristol Myers Squibb, Eisai, Genzyme, Merck, Novartis, Sun Pharma, Eisai, Regeneron, TRM Oncology, Ayala Pharmaceuticals, AstraZeneca, Sanofi, CureVac, Prelude Therapeutics, Kura Oncology, McGivney Global Advisors, Rgenta, AffyImmune Therapeutics, Exelixis, Cellestia, InxmedSpeakers’ Bureau: Medscape, Omniprex America, NovartisResearch Funding: Lilly, Genentech/Roche (Inst), AstraZeneca, Allos Therapeutics, Astellas Pharma, Ayala Pharmaceuticals, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Elevar Therapeutics, Kolltan Pharmaceuticals, Kura Oncology, Merck, Novartis, PfizerTravel, Accommodations, Expenses: Janssen Oncology, Merck, Kura Oncology, Ignyta, Ayala Pharmaceuticals, Klusa Pharma Marek DedecjusHonoraria: Sanofi/Aventis, Bayer, Berlin-ChemieResearch Funding: AstraAzeneca/Merck, Exelixis Lori J. WirthConsulting or Advisory Role: Merck, Loxo, Blueprint Medicines, Eisai, Lilly, Bayer, ExelixisResearching Funding: Checkmate Pharmaceuticals (Inst), Lilly (Inst), Ayala Pharmaceuticals (Inst), Eisai (Inst)Expert Testimony: EisaiOther Relationship: PDS Biotechnology R. Michael TuttleResearch Funding: Elesta (Inst) Fernanda VaismanConsulting or Advisory Role: AstraZeneca/Merck, Ipsen, Lilly, Bayer HealthSpeaker’s Bureau: Bayer, AstraZeneca/Merck, Sanofi, United Medical Lars BastholtResearch Funding: Bristol Myers Squibb (Inst) Andrew G. GianoukakisConsulting or Advisory Role: Eisai, Exelixs Patrice RodienConsulting or Advisory Role: Eisai EuropeResearch Funding: Pfizer (Inst) Ralf PaschkeConsulting or Advisory Role: Bayer, EisaiResearching Funding: Bayer (Inst)Patents, Royalties, Other Intellectual Property: Licensing fee for a diagnostic testRossella EliseiConsulting or Advisory Role: EISAI, Genezyme, Loxo, Ipsen, Bayer, Lilly Karen SoEmployment: AstraZenecaStock and Other Ownership Interests: AstraZeneca Danielle CarrollEmployment: AstraZeneca/MedImmune, Azeria therapeutics (I)Leadership: Azeria therapeutics (I)Stock and Other Ownership Interests: AstraZeneca/MedImmune, Azeria Therapeutics (I)Honoraria: AstraZeneca (I)Consulting or Advisory Role: Azeria therapeutics (I)Research Funding: AstraZeneca (I)Patents, Royalties, Other Intellectual Property: Royalties from Active Motif (I), Compositions featuring an attenuated Newcastle disease virus and methods of use for treating neoplasia, Anti-cxc chemokine-2 binding molecules and uses thereof Tina HoveyEmployment: PhastarConsulting or Advisory Role: AstraZenecaResearch Funding: AstraZeneca James A. FaginHonoraria: Eisai EuropeConsulting or Advisory Role: Loxo OncologyPatents, Royalties, Other Intellectual Property: 3. MSK Ref. SK 2014-024-03 Title: Treatment of H-RAS-Driven Tumors. Application Number: 15/305,788. 3. Anti-TSHR Multispecific Antibodies and Uses Thereof, provisional patent.No other potential conflicts of interest were reported.