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.
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 (ClinicalTrials.gov 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.
- 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.
- 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
- 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