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Multicenter Randomized Double-Blind Phase III Trial of Donafenib in Progressive Radioactive Iodine-Refractory Differentiated Thyroid Cancer.

Department of Nuclear Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College (PUMC) Hospital, Chinese Academy of Medical Sciences & PUMC, Beijing, China. Department of Oncology, Cancer Center of Bayi Hospital, Nanjing Chinese Medicine University, Nanjing, China. Department of Nuclear Medicine, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China. Department of Nuclear Medicine, Hunan Cancer Hospital, Changsha, China. Department of Nuclear Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. Department of Nuclear Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Department of Nuclear Medicine, West China Hospital of Sichuan University, Chengdu, China. Department of Nuclear Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China. Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Nuclear Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. Department of Nuclear Medicine, Yunnan Cancer Hospital, Kunming, China. Department of Nuclear Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China. Department of Nuclear Medicine, Affiliated Hospital of Guilin Medical University, Guilin, China. Department of Oncology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China. Department of Nuclear Medicine, Zhejiang Cancer Hospital, Hangzhou, China. Department of Medical Oncology, Cancer Hospital Chinese Academy of Medical Sciences, Beijing, China. Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. Department of Nuclear Medicine, China-Japan Union Hospital of Jilin University, Changchun, China. Department of Medical Oncology, Affiliated Sixth People's Hospital, Shanghai Jiaotong University, Shanghai, China. Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China. Department of Oncology, The Second Hospital of Anhui Medical University, Hefei, China. Department of Nuclear Medicine, Harbin Medical University Cancer Hospital, Harbin, China. Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, China. Department of Nuclear Medicine, Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China. Department of Otolaryngology-Head and Neck Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China. Department of Nuclear Medicine, The First Hospital of Shanxi Medical University, Taiyuan, China. Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China. Department of Head and Neck Surgery, Jiangsu Cancer Hospital, Nanjing, China. Department of Medical Oncology, Sir Run Run Shaw Hospital Zhejiang University School of Medicine, Hangzhou, China. Department of Head and Neck Surgery, Liaoning Cancer Hospital and Institute, Shenyang, China. Department of Nuclear Medicine, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China. Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China. Department of Nuclear Medicine, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China. Department of Thyroid Surgery, The First Hospital of Jilin University, Changchun, China. Department of Oncology, Changsha Central Hospital, Changsha, China. Department of Clinical Research, Suzhou Zelgen Biopharmaceuticals Co., Ltd, Suzhou, China. Department of Biostatistics, Suzhou Zelgen Biopharmaceuticals Co., Ltd, Suzhou, China.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2023;(15):2791-2799
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Abstract

PURPOSE The phase II/III study of donafenib was initiated when there was no available treatment indicated for Chinese patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC). Donafenib, an oral tyrosine kinase inhibitor (TKI), showed good efficacy and tolerability in the phase II study. We aimed to further evaluate the antitumor activity and safety of donafenib in Chinese patients with RAIR-DTC. PATIENTS AND METHODS This multicenter, double-blind, placebo-controlled, phase III study enrolled 191 patients with progressive RAIR-DTC and randomized in a ratio of 2:1 to donafenib (300 mg twice daily, n = 128) or matched placebo (n = 63). An open-label donafenib treatment period was allowed upon disease progression. The primary endpoint was progression-free survival (PFS) assessed by the independent review committee. The second endpoints include objective response rate (ORR), disease control rate (DCR), safety, etc. RESULTS Donafenib demonstrated prolonged median PFS over placebo [12.9 vs. 6.4 months; hazard ratio (HR), 0.39; 95% confidence interval (CI), 0.25-0.61; P < 0.0001] in Chinese patients with RAIR-DTC. Improved ORR (23.3% vs. 1.7%; P = 0.0002) and DCR (93.3% vs. 79.3%; P = 0.0044) were observed in the donafenib group over placebo. For donafenib, the most common grade ≥ 3 treatment-related adverse events (AE) included hypertension (13.3%) and hand-foot syndrome (12.5%), 42.2% underwent dose reduction or interruption, and 6.3% experienced discontinuation. CONCLUSIONS Donafenib was well-tolerated and demonstrated clinical benefit in terms of improved PFS, ORR, and DCR in patients with RAIR-DTC. The results suggest that donafenib could be a new treatment option for patients with RAIR-DTC.

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