Donafenib appears effective in patients with progressive, locally advanced or metastatic radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC), results of the phase 3 DIRECTION study suggest.1 

Compared with placebo, donafenib improved the objective response rate and progression-free survival (PFS) in RAIR-DTC patients, whether or not they had prior tyrosine kinase inhibitor (TKI) treatment. 

These results suggest donafenib could be an alternative treatment for patients with progressive RAIR-DTC, according to Yansong Lin, MD, of Peking Union Medical College Hospital in Beijing, China. Dr Lin presented the results at ESMO Congress 2022. 

Continue Reading

Dr Lin noted that donafenib is a deuterated derivative of sorafenib that proved superior to sorafenib in a phase 3 trial of hepatocellular carcinoma.2 Donafenib also demonstrated efficacy in a phase 2 trial of RAIR-DTC.3

In the phase 3 DIRECTION trial ( Identifier: NCT03602495), the researchers enrolled 191 patients with locally advanced or metastatic RAIR-DTC and disease progression within the past 14 months.1 

The patients were randomly assigned 2:1 to donafenib at 300 mg twice daily (n=128) or placebo (n=63). Patients whose disease progressed on placebo could cross over to receive donafenib.

At baseline, the median age was 59 (range, 31-76) years in the donafenib arm and 60 (range, 27-74) years in the placebo arm. Most patients had not received prior TKI therapy (81.3% and 82.5%, respectively), and most had papillary DTC (81.3% and 71.4%).

The primary endpoint was PFS. The median PFS was 12.9 months in the donafenib arm and 6.4 months in the placebo arm (hazard ratio [HR], 0.39; 95% CI, 0.25-0.61; P <.0001). 

The improvement in PFS was seen whether or not patients had received prior TKI therapy. Among TKI-naïve patients, the median PFS was 18.3 months in the donafenib arm and 7.4 months in the placebo arm (HR, 0.45; 95% CI, 0.27-0.73). Among TKI-exposed patients, the median PFS was 11.0 months and 3.7 months, respectively (HR, 0.23; 95% CI, 0.09-0.61). 

The objective response rate was higher in the donafenib arm than in the placebo arm as well — 23.3% and 1.7%, respectively (P=.0002). All responses were partial responses.

The median overall survival was not reached due to few events and the crossover design, Dr Lin said. The 18-month overall survival rate was 88.3% in the donafenib arm and 73.5% in the placebo arm. 

More than 60% of patients from the placebo arm crossed over to the donafenib arm and showed a PFS benefit with donafenib. 

Dr Lin noted that the average daily dose of donafenib was 522 mg/day, which accounted for 87.0% of the initial dose, indicating patient adherence. In the double-blind period, 66.4% of patients receiving donafenib maintained the initial dose. 

Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 43.8% of patients in the donafenib arm and 1.6% of patients in the placebo arm. The most common grade 3-4 TRAEs in the donafenib arm were hypertension (13.3%) and hand-foot syndrome (12.5%).  

Disclosures: This research was supported by Suzhou Zelgen Biopharmaceuticals. Two study authors declared affiliations with the company. Please see the original reference for a full list of disclosures.


  1. Lin Y, Yang H, Shi F, et al. Donafenib in locally advanced/metastatic, radioactive iodine-refractory, differentiated thyroid cancer: A randomized, double-blind, placebo-controlled, multi-center phase III clinical trial (DIRECTION). Presented at ESMO 2022; September 9-13, 2022. Abstract 1644O.
  2. Qin S, Bi F, Gu S, et al. Donafenib versus sorafenib in first-line treatment of unresectable or metastatic hepatocellular carcinoma: A randomized, open-label, parallel-controlled phase II-III trial. J Clin Oncol. 2021;39(27):3002-3011. doi:10.1200/JCO.21.00163
  3. Lin Y-S, Yang H, Ding Y, et al. Donafenib in progressive locally advanced or metastatic radioactive iodine-refractory differentiated thyroid cancer: Results of a randomized, multicenter phase II trial. Thyroid. 2021;31(4):607-615. doi:10.1089/thy.2020.0235