Donafenib in Locally Advanced/Metastatic Radioactive Iodine-Refractory Differentiated Thyroid Cancer: A Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Phase III Clinical Trial (DIRECTION)

Abstract Background No available treatment existed in Chinese patients with progressive radioactive iodine–refractory differentiated thyroid cancer (RAIR-DTC) in terms of both affordability and safety upon the initiation of DIRECTION study. Donafenib is an oral tyrosine kinase inhibitor (TKI) with superior efficacy over sorafenib in hepatocellular carcinoma (HCC) phase III study. This study aimed to evaluate its antitumour activity and safety in Chinese RAIR-DTC patients. Methods The sequential phase II/III design as a whole protocol was approved by Center for Drug Evaluation (CDE) of the Chinese National Medical Products Administration (NMPA) by April 25, 2016. The phase II study was finished by March 2018. For the multicenter, double blind, placebo controlled, phase III study, 191 patients with locally advanced or metastatic RAIR-DTC progressed within the past 14 months were enrolled as per protocol design. Along with the approval sorafenib in China during the process of this study, sorafenib was accordingly introduced as an alternative to all the following patients for their option. Two interim analyses were planned. Patients were 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. Analysis was based on the intention-to-treat population (ITT). The second endpoint including (ORR), (OS), (DCR), safety, et al. 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 RAIR-DTC patients either with prior TKIs (11.0 vs 3.7 months, HR 0.23, 95% CI 0.09–0.61) or not (18.3 vs 7.4 months, HR 0.45, 95% CI 0.27–0.73). Improved objective response rate (ORR) was observed in the donafenib group over placebo (23.3% vs 1.7%, p = 0.0002). The most common grade ≥ 3 treatment-related adverse events in the donafenib group included hypertension (13.3%) and HFS (12.5%). Of the donafenib group, 6.3% experienced discontinuation and 42.2% for dose reduction or interruption. The average daily dosage accounted for 87.0% of the initial dose, indicating the high adherence of patients to donafenib. Conclusions Donafenib meaningfully improved progression-free survival in patients with RAIR-DTC, particularly in those with prior TKIs. The high adherence of initial dose of donafenib as a result of the low occurrence of grade 3 or above adverse events guaranteed its sustainable anti-tumour effect during treatment.