A Summary of State-of-the-Art Clinical Trials for Advanced Thyroid Cancers, Organized by the International Thyroid Oncology Group

Clinical Thyroidology®Vol. 35, No. 9 EditorialFree AccessA Summary of State-of-the-Art Clinical Trials for Advanced Thyroid Cancers, Organized by the International Thyroid Oncology GroupLaura Boucai, Ashish Chintakuntlawar, David C. Shonka, Jr., and Members, ITOGLaura Boucai Division of Subspecialty Medicine, Endocrinology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, U.S.A.Search for more papers by this author, Ashish Chintakuntlawar Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, U.S.A.Search for more papers by this author, David C. Shonka, Jr. Department of Otolaryngology—Head & Neck Surgery, University of Virginia Health System, Charlottesville, Virginia, U.S.A.Search for more papers by this author, and Members, ITOGPublished Online:13 Sep 2023https://doi.org/10.1089/ct.2023;35.350-354AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail This invited editorial provides a summary of the history and mission of the International Thyroid Oncology Group (ITOG), highlighting the continuing collaboration between Clinical Thyroidology and ITOG.The International Thyroid Oncology Group (ITOG, www.itog.org) is a not-for-profit organization founded in 2006 whose mission is to find a cure for the most challenging thyroid cancers. The group does this through the collaborative efforts of a multidisciplinary team of endocrinologists, surgeons, medical and radiation oncologists, basic scientists, and advocates by designing, coordinating, and prioritizing state-of-the-art clinical trials and correlative science studies.The organization grew out of a need for novel treatments in advanced thyroid cancer and was ultimately inspired by thyroid cancer patients such as Ms. Jean Vicks—a mother, a coach, and an avid outdoor enthusiast. After the initial meeting in 2003, the organization's inception was formalized at an inaugural meeting in Atlanta, Georgia, in 2006. The founding members included Drs. Robert Gagel, Samuel Wells, Jr., and Steven Sherman and Mr. Dwight Vicks. Since then, ITOG's membership has grown to include prominent scientists and leading clinicians in the field of thyroid cancer.Currently, ITOG's membership includes 132 leading physicians, scientists, and advocates from 16 countries: Australia, Brazil, Canada, China, France, Germany, Israel, Italy, the Netherlands, Saudi Arabia, Singapore, South Korea, Spain, Switzerland, the United Kingdom, and the United States. ITOG is organized into 12 committees and 7 task forces that work toward the common goal of finding new therapies for thyroid cancer, training the next generation of clinicians and scientists, and raising public awareness about the importance of thyroid cancer research.Through the tireless efforts and commitment of its members and advocates, ITOG has successfully completed seven clinical trials (Table 1). The “Combination Targeted Therapy With Pembrolizumab and Lenvatinib in Progressive, Radioiodine-Refractory (RAIR) Differentiated Thyroid Cancers (DTC): A Phase II Study” (NCT02973997; principal investigator [PI]: Dr. Bryan Haugen) is an open-label, single-arm study of 60 patients with progressive RAIR DTC that intends to investigate the clinical efficacy of the combination of immunotherapy with a multikinase inhibitor in lenvatinib-naive patients (cohort 1) and to determine the overall response rate (ORR) when adding pembrolizumab to the treatment of patients whose disease continues to progress on lenvatinib alone (cohort 2). Lenvatinib alone was also tested as a therapeutic agent for anaplastic thyroid cancer in a phase 2 study (NCT02657369), but that study was halted for futility, as the minimum ORR threshold of 15% was not met upon interim analysis (1). The combination of ipilimumab, nivolumab, and cabozantinib for the treatment of advanced RAIR DTC was tested in a phase 2 study and results are awaited (NCT03914300). The first randomized trial to evaluate the benefit of a redifferentiating strategy is a double-blind, phase 2 study of radioactive iodine (RAI) with and without selumetinib for the treatment of RAI-avid metastatic thyroid cancers (NCT02393690; PI: Dr. Alan Ho). Another ITOG-led phase 2 study assessed the efficacy of cabozantinib in patients with RAIR DTC whose disease progressed on prior vascular endothelial growth factor receptor (VEGFR)–targeted therapy (NCT01811212; PI: Manisha Shah). This study evaluated the ORR of cabozantinib in 25 patients with RAIR DTC and found that 40% had a partial response and 52% had stable disease while taking this drug (2). “Efficacy of Selpercatinib in RET-Altered Thyroid Cancers” (NCT03157128; PI: Dr. Lori Wirth and Protocol-Specific Steering Committee) was an open-label study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of selpercatinib in participants with advanced solid tumors, including rearranged during transfection (RET)–fusion-positive solid tumors, medullary thyroid cancer (MTC), and other tumors with RET activation. In previously treated MTC, the ORR was 69% (95% CI, 55–81) and the 1-year progression-free survival (PFS) was 82% (95% CI, 69–90). In patients with previously treated DTC, the ORR was 79% (95% CI, 54–94) and the 1-year PFS was 64% (95% CI, 37–82) (3). Finally, “The Randomized Phase II Study of Sorafenib with or without Everolimus in Patients with Radioactive Iodine Refractory Hurthle Cell Thyroid Cancer” (NCT02143726; PI: Dr. Eric Sherman) is an open-label, randomized trial of 35 patients that investigates the effects of using the mTOR inhibitor everolimus along with the multikinase inhibitor sorafenib tosylate versus using sorafenib tosylate alone in treating patients with advanced RAI-refractory oncocytic carcinoma of the thyroid.Table 1. ITOG Completed Studies.TrialClinicalTrials.gov No.Drug(s)StatusThe Combination Targeted Therapy with Pembrolizumab and Lenvatinib in Progressive, Radioiodine-Refractory (RAIR) Differentiated Thyroid Cancers (DTC): A Phase II StudyNCT02973997Pembrolizumab and lenvatinibAccrual completed; estimated completion date: October 8, 2023Open-Label, Single-Arm, Multicenter, Phase II Trial of Lenvatinib for the Treatment of Patients with Anaplastic Thyroid CancerNCT02657369LenvatinibCompleted; results published (1)Phase II Study of XL184 (Cabozantinib) in Combination with Nivolumab and Ipilimumab (CaboNivoIpi) in Patients with Radioiodine-Refractory Differentiated Thyroid Cancer Whose Cancer Progressed after One Prior VEGFR-Targeted TherapyNCT03914300Cabozantinib, ipilimumab, nivolumabAccrual completed; estimated completion date: January 15, 2024Randomized Double-Blind Phase II Study of Radioactive Iodine (RAI) in Combination with Placebo or Selumetinib for the Treatment of RAI-Avid Recurrent/Metastatic Thyroid CancersNCT02393690SelumetinibAccrual completed; estimated completion date: December 31, 2023Cabozantinib as Salvage Therapy for Patients with Tyrosine Kinase Inhibitor–Refractory Differentiated Thyroid Cancer: Results of a Multicenter Phase II International Thyroid Oncology Group TrialNCT01811212CabozantinibCompleted; results published (2)Efficacy of Selpercatinib in RET-Altered Thyroid CancersNCT03157128SelpercatinibRecruiting; estimated completion date: September 1, 2024 Some results published (3)Randomized Phase II Study of Sorafenib with or without Everolimus in Patients with Radioactive Iodine Refractory Hurthle Cell Thyroid CancerNCT02143726Sorafenib and everolimusAccrual completed; estimated completion date: August 6, 2024Three ITOG clinical trials are currently enrolling patients (Table 2). “Selpercatinib before Surgery for the Treatment of RET-Altered Thyroid Cancer” (NCT04759911; PI: Dr. Mark Zafereo) studies the ability of the selective RET inhibitor selpercatinib to decrease the size of locally invasive RET-mutated thyroid cancers to facilitate a surgical resection. This study is currently enrolling patients at MD Anderson Cancer Center and University of Michigan Health System. “Restoration of Radioiodine Uptake with Selpercatinib in RET Fusion-Positive Radioiodine-Refractory Thyroid Cancer: A Phase 2 Study Performed in Collaboration with the International Thyroid Oncology Group” (NCT05668962; PI: Dr. Lori Wirth) studies the efficacy of the selective RET inhibitor selpercatinib to restore RAI uptake and allow for RAI treatment in patients with RET fusion–positive RAIR progressive follicular-cell–derived thyroid cancer. The study is currently enrolling patients at Massachusetts General Hospital. Finally, “A Phase 1 Trial of Concurrent Intensity Modulated Radiation Therapy (IMRT) and Dabrafenib/Trametinib in BRAF Mutated Anaplastic or Poorly Differentiated Thyroid Cancer” (NCT03975231; PI: Dr. Terrance Williams) studies the effect of adding the BRAF and MEK inhibitors dabrafenib and trametinib to IMRT for the treatment of the most advanced forms of thyroid cancer that are BRAF V600E–mutated. The study is currently enrolling patients at City of Hope Medical Center and will soon be opening at Ohio State University and MD Anderson Cancer Center.Table 2. Current ITOG Clinical Trials.TrialTrial ClinicalTrials.gov No.Drug(s)StatusNeoadjuvant Treatment with Selpercatinib in RET-Altered Thyroid CancersNCT04759911SelpercatinibRecruiting at MD Anderson Cancer Center and University of Michigan Health SystemRestoration of Radioiodine Uptake with Selpercatinib in RET Fusion-Positive Radioiodine-Refractory Thyroid Cancer: A Phase 2 Study Performed in Collaboration with the International Thyroid Oncology Group (ITOG)NCT05668962SelpercatinibRecruiting at Massachusetts General HospitalA Phase 1 Trial of Concurrent Intensity Modulated Radiation Therapy (IMRT) and Dabrafenib/Trametinib in BRAF Mutated Anaplastic or Poorly Differentiated Thyroid CancerNCT03975231Dabrafenib, trametinib, and intensitymodulated radiation therapyRecruiting at City of Hope Medical Center; soon to open at Ohio State University and MD Anderson Cancer CenterWhile the focus of ITOG is the development of clinical trials targeted to find cures for progressive thyroid cancer, the creation of patient registries will critically inform the biology and clinical behavior of the disease. The MTC registry is led by Drs. Julie Ann Sosa and Elizabeth Grubbs; the acquired resistance to kinase inhibitors registry is led by Drs. Lori Wirth, Rory Clifton-Bligh, and Matti Gild; and the redifferentiation registry is led by Drs. Sophie Leboulleux, Lori Wirth, and Alan Ho. A neoadjuvant clinical registry is under development. We invite the medical community to get involved in ITOG and benefit from the expertise of this group of physicians, scientists, and advocates who devote their efforts to finding cures for thyroid cancer. The diverse community of ITOG members is committed to ensuring inclusive recruitment of patients to clinical trials and strives to address inequalities inherent in the geographic distribution of resources. ITOG welcomes innovative ideas, different outlooks, and a broad participation.Disclosures: The authors have no relevant conflicts of interest to declare.References1. Wirth LJ, Durante C, Topliss DJ, et al. 2022 Lenvatinib for the Treatment of Radioiodine-Refractory Differentiated Thyroid Cancer: Treatment Optimization for Maximum Clinical Benefit. Oncologist. 27:565-572. Crossref, Medline, Google Scholar2. Cabanillas ME, de Souza JA, Geyer S, et al. 2017 Cabozantinib As Salvage Therapy for Patients With Tyrosine Kinase Inhibitor-Refractory Differentiated Thyroid Cancer: Results of a Multicenter Phase II International Thyroid Oncology Group Trial. J Clin Oncol. 35:3315-3321. Crossref, Medline, Google Scholar3. Wirth LJ, Sherman E, Robinson B, et al. 2020 Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. N Engl J Med. 383:825-835. Crossref, Medline, Google ScholarFiguresReferencesRelatedDetails Volume 35Issue 9Sep 2023 Information© Copyright 2023, Mary Ann Liebert, Inc.To cite this article:Laura Boucai, Ashish Chintakuntlawar, David C. Shonka, Jr., and Members, ITOG.A Summary of State-of-the-Art Clinical Trials for Advanced Thyroid Cancers, Organized by the International Thyroid Oncology Group.Clinical Thyroidology®.Sep 2023.350-354.http://doi.org/10.1089/ct.2023;35.350-354Published in Volume: 35 Issue 9: September 13, 2023PDF download