Redifferentiation therapy in unresectable or metastatic radioactive iodine refractory thyroid cancer: an International Thyroid Oncology Group statement

Sophie Leboulleux¹, Laura Boucai², Naifa Busaidy³, Cosimo Durante⁴, James A Fagin⁵, Sasan Fazeli⁶, Andrew G Gianoukakis⁷, Bryan R Haugen⁸, Hyunseok Kang⁹, Bhavana Konda¹⁰, Theodore W Laetsch¹¹, Laura Locati¹², Mabel Ryder¹³, Christine Spitzweg¹⁴, Francis P Worden¹⁵, Lori Wirth¹⁶, Alan Ho¹⁷

Affiliations

¹ Department of Medicine, Endocrinology and Diabetology Service, Geneva University Hospitals and Univerisity of Geneva, Geneva, Switzerland. Electronic address: sophie.leboulleux@hug.ch.
² Department of Medicine, Endocrinology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³ Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
⁵ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁶ Department of Clinical Diabetes, Endocrinology & Metabolism, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
⁷ Division of Endocrinology, Diabetes and Metabolism, David Geffen School of Medicine at UCLA Harbor-UCLA Medical Center, Los Angeles, CA, USA.
⁸ Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, Aurora, CO, USA.
⁹ Department of Medicine, University of California at San Francisco, San Francisco, CA, USA.
¹⁰ Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
¹¹ Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹² Medical Oncology Unit, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy.
¹³ Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN, USA.
¹⁴ Department of Internal Medicine IV, LMU Munich, Germany; Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA.
¹⁵ Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.
¹⁶ Harvard Medical School, Boston, MA, USA; Center for Head and Neck Cancers, Massachusetts General Hospital, Boston, MA, USA.
¹⁷ Department of Medicine, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY, USA; Head and Neck Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

PMID: 40318680
DOI: 10.1016/S2213-8587(25)00064-6

Free article

Review

Redifferentiation therapy in unresectable or metastatic radioactive iodine refractory thyroid cancer: an International Thyroid Oncology Group statement

Sophie Leboulleux et al. Lancet Diabetes Endocrinol. 2025 Jun.

Free article

. 2025 Jun;13(6):516-527.

doi: 10.1016/S2213-8587(25)00064-6. Epub 2025 Apr 30.

Authors

Affiliations

¹ Department of Medicine, Endocrinology and Diabetology Service, Geneva University Hospitals and Univerisity of Geneva, Geneva, Switzerland. Electronic address: sophie.leboulleux@hug.ch.
² Department of Medicine, Endocrinology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³ Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
⁵ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁶ Department of Clinical Diabetes, Endocrinology & Metabolism, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
⁷ Division of Endocrinology, Diabetes and Metabolism, David Geffen School of Medicine at UCLA Harbor-UCLA Medical Center, Los Angeles, CA, USA.
⁸ Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, Aurora, CO, USA.
⁹ Department of Medicine, University of California at San Francisco, San Francisco, CA, USA.
¹⁰ Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
¹¹ Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹² Medical Oncology Unit, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy.
¹³ Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN, USA.
¹⁴ Department of Internal Medicine IV, LMU Munich, Germany; Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA.
¹⁵ Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.
¹⁶ Harvard Medical School, Boston, MA, USA; Center for Head and Neck Cancers, Massachusetts General Hospital, Boston, MA, USA.
¹⁷ Department of Medicine, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY, USA; Head and Neck Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

PMID: 40318680
DOI: 10.1016/S2213-8587(25)00064-6

Abstract

In patients with follicular cell-derived thyroid cancer that have distant metastases and no iodine uptake, redifferentiation-ie, the restoration of tumoural ¹³¹I uptake with systemic therapy-is now possible. The use of mitogen-activated protein kinase (MAPK) inhibitors for a short period of time before the administration of high activity ¹³¹I shows promising results with iodine uptake restoration and tumour response. Redifferentiation has been used in patients with BRAF-mutated and RAS-mutated tumours in prospective trials and in the case of patients with RET or NTRK fusions. The iodine uptake restoration ranges from 33% to 95%, and tumour response rates from 11% to 80%. There is substantial variability between trials with regards to inclusion criteria, duration of redifferentiation drug therapy, activity of radioactive iodine, and use of dosimetry. Randomised studies are missing to clearly establish the effectiveness and applicability of redifferentiation. Thus, long-term studies are needed to establish the most effective redifferentiation protocols. The objectives of this Review are to: (1) provide a comprehensive review of the available results from prospective trials and case reports, including results regarding the restoration of radioiodine uptake and treatment efficacy (morphological and biological); (2) describe the differences in redifferentiation trial design between studies and discuss their potential impact on treatment efficacy; (3) describe the implications and limitations of dosimetry; and (4) outline the key questions to be addressed in future redifferentiation trials.

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Conflict of interest statement

Declaration of interests SL reports consulting fees from Eisai, Lilly, Bayer, and IPSEN; financial support from Recordati for attending meetings; and is a member of the International Thyroid Oncology Group redifferentiation Taskforce. NB reports research grant from GlaxoSmithKline; and consulting fees from Eisai and Exelixis. CD reports participation on advisory boards of Eisai and Ipsen; and honoraria for lectures from Eisai and Lilly. SF reports receipt of vemurafenib and cobimetinib from Genentech for a clinical trial and consulting fees from Novartis. BRH reports research grant from Afirma; participation on advisory board for Eisai; and is protocol committee chair and on the executive committee of International Thyroid Oncology Group. HK reports grants to the institution from Lilly, NeoImmuneTech, Remix Therapeutics, PDS Biotechnology, and Merus; consulting fees from PIN therapeutics and Coherus; and participation on a data safety monitoring board for MitoImmune and on an advisory board for HLB Group. BK reports grants to the institution from Merck, Eisai, and Xencor. TWL reports grants from Bayer, Pfizer, Turning Point Therapeutics, Lilly, Roche–Genentech, Taiho Oncology, Novartis, BioAtla, Hoffmann-LaRoche, Jazz Pharmaceuticals, Exelixis, and Adaptimmune; and consulting fees from Advanced Microbubbles, Bayer, MassiveBio, Jazz Pharmaceuticals, GentiBio, ITM Oncologics, and GSK. LL reports honoraria for lectures from MSD, Lilly, Sunpharma, Novartis, and Seagan; participation on an advisory board for Ipsen, Eisai, Roche, and Bayer; financial support for attending meetings from Gilead. CS reports honoraria for lectures and advisory boards from Eisai, Lilly, Ipsen, Sanofi, Roche, and Bayer. FW reports participation on advisory boards for Eisai, Merck, Bayer, Exelexis, and Loxo; travel expenses from Merck and Exelexis; and consulting fees from Eisai. LW reports consulting fees for serving on the advisory boards of Merck, Eisai, Eli Lilly, Exelixis, Coherus, METIS Precision Medicine, Tome Bioscience, EMD Serono, Ellipses Pharma, Illumina, and Neste; and consulting fees for participation on a data safety monitoring board for PDS Biotechnology. AH reports consulting fees from Rgenta Therapeutics and ExpertConnect; payment or honoraria for lectures from Physician Education Resource, Chinese American Hematologist and Oncologist Network, Northwestern, Endocrine Society, University of Pittsburg Medical Center, and New York University; support for attending meetings or travel, or both, from Remix Therapeutics; patents planned, issued or pending for Lesional dosimetry methods for tailoring targeted radiotherapy in cancer; participation on a data safety monitoring board or advisory board for Affyimmune, Kura Oncology, Nested Therapeutics, Coherus Biosciences, Exelixis, Eisai, Merck, Elevar Therapeutics, Prelude Therapeutics, and Ayala; leadership or fiduciary role on boards for International Thyroid Oncology Group (board member); stock or stock options from Rgenta Therapeutics. January, 2021, stock options were provided for consulting (options were cancelled in January, 2023, with 100 USD payout that was donated to the Conquer Cancer Foundation); provision of drug for preclinical investigation from Daiichi Sankyo; and other financial or non-financial interests from Lepu Biopharma and Hookipa (accepted meals). LB, JAF, AGG, and MR declare no competing interests.

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Redifferentiation therapy in unresectable or metastatic radioactive iodine refractory thyroid cancer: an International Thyroid Oncology Group statement

Affiliations

Redifferentiation therapy in unresectable or metastatic radioactive iodine refractory thyroid cancer: an International Thyroid Oncology Group statement

Authors

Affiliations

Abstract

Conflict of interest statement

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Medical

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