Donafenib, an oral multi-kinase inhibitor that targets Raf/MEK/ERK, VEGFR, PDGFR, has shown potent efficacy and well-tolerated safety profile in patients with progressive locally advanced/metastatic radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) in a phase II study. The DIRECTION study aims to evaluate the efficacy and safety of donafenib and initiated when there was no available TKI for Chinese RAIR-DTC patients.
In this randomized, double-blind, placebo-controlled, multi-center phase III trial, eligible patients were randomized (2:1) to receive donafenib (300 mg) or placebo twice daily until intolerable toxicity or disease progression. The primary endpoint was PFS, the second endpoints including ORR, OS, safety, et al.
From July 2018 to February 2021, a total of 191 patients were randomized (donafenib, 128; placebo, 63) which is the largest Chinese RAIR-DTC patients enrolled in trials so far. The primary end point was met upon pre-planned second interim analysis when 67% PFS events were observed. Donafenib significantly prolonged the median IRC-PFS than placebo (12.9 vs. 6.4 months, HR=0.39, 95% CI 0.25-0.61, p<0.0001), either in TKI-naïve subgroup (18.3 vs. 7.4 months, HR=0.45, 95% CI 0.27-0.73), or in TKI-used subgroup (11.0 vs. 3.7 months, HR=0.23, 95% CI 0.09-0.61), suggesting its potential as a second line therapy. The ORR of donafenib was higher than placebo (23.3% vs 1.7%, p=0.0002). The 18-month survival rate for donafenib vs. placebo was 88.3% vs. 73.5%, with the median overall survival not reached. Regarding the drug adherence and safety, the average daily dose of donafenib was 522 mg/day, accounting for 87.0% of the initial dose (600 mg/day), indicating its well adherence. Treatment-related adverse events (TRAEs) of Grade≥3 occurred in 56 (43.8%) patients in donafenib group, with hypertension (13.3%) and palmar-plantar erythrodysaesthesia syndrome (12.5%) the most common. No treatment-related death was observed.
Donafenib well balanced the efficacy and safety, suggesting its potential to be an alternative for patients with progressive RAIR-DTC.
Clinical trial identification
Legal entity responsible for the study
Zelgen Biopharmaceuticals Co., Ltd.
L. Wu, L. Liu: Financial Interests, Personal and Institutional, Full or part-time Employment: Suzhou Zelgen Biopharmaceuticals Co., Ltd. All other authors have declared no conflicts of interest.