Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, China.
Department of Nuclear Medicine, Henan Cancer Hospital, Zhengzhou, China.
Thyroid. 2021 Apr;31(4):607-615. doi: 10.1089/thy.2020.0235. Epub 2020 Oct 15.
An unmet need for more effective and affordable kinase inhibitors remains in patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) in China, where only sorafenib is approved for this indication. This study evaluated the 24-week objective response rate (ORR) to donafenib-a new, domestic multikinase inhibitor-in the treatment of locally advanced or metastatic RAIR-DTC in patients with measurable lesions. Two dose regimens (300 mg twice daily vs. 200 mg twice daily) were used to determine its optimal dosage and safety for further phase III studies. This study was a randomized, open-label, multicenter phase II trial. Thirty-five adult RAIR-DTC patients with at least one measurable targeted lesion according to RECIST 1.1 were enrolled from 12 centers in China and randomized to receive either 200 mg (17 patients) or 300 mg (18 patients) of donafenib orally twice daily for 24 weeks. The primary endpoint was ORR, and the secondary endpoints included progression-free survival (PFS) among others. Additionally, biochemical (serum thyroglobulin) and structural (total tumor diameter [TTD]) responses were assessed, change (ΔTTD) rates were calculated, and safety was evaluated. The ORRs for the 200- and 300-mg arms were 12.5% and 13.33% ( = 1.000), respectively. The 300-mg arm had a nonsignificant, longer median PFS than the 200-mg arm (14.98 months vs. 9.44 months) ( = 0.351). There was a trend toward more tumor shrinkage in the 300-mg arm compared with the 200-mg arm (average ΔTTD rate -0.52 ± 0.71 vs. -0.04 ± 1.55 mm/month, = 0.103). Most treatment-related adverse events (AEs) in both arms were grades 1-2. The most common grade 3 treatment-related AEs in both arms were palmar-plantar erythrodysesthesia and hypertension; the sum occurrence rates of these two AEs in the 200-mg and 300-mg arms were 11.43% and 22.86%, respectively. Donafenib was generally well tolerated. Both donafenib regimens demonstrated similar efficacy in terms of the ORR in locally advanced or metastatic RAIR-DTC. The results warrant further studies on donafenib as a new, feasible treatment option for RAIR-DTC patients. Clinical Trials.gov IDs: NCT02870569; CTR20160220.
在中国，进展性放射性碘难治性分化型甲状腺癌（RAIR-DTC）患者仍存在对更有效和更经济的激酶抑制剂的需求，目前仅索拉非尼被批准用于该适应证。本研究评估了新型国产多激酶抑制剂——多纳非尼在有可测量病灶的局部晚期或转移性 RAIR-DTC 患者中的 24 周客观缓解率（ORR）。采用两种剂量方案（300mg，每日 2 次；200mg，每日 2 次），以确定其进一步开展 III 期研究的最佳剂量和安全性。本研究为一项随机、开放标签、多中心 II 期临床试验。从中国 12 家中心共招募了 35 名至少有一个符合 RECIST 1.1 标准的可测量靶病灶的 RAIR-DTC 成年患者，并将其随机分为两组，分别接受多纳非尼 200mg（17 例）或 300mg（18 例），每日口服 2 次，疗程 24 周。主要终点为 ORR，次要终点包括无进展生存期（PFS）等。此外，还评估了生化（血清甲状腺球蛋白）和结构（总肿瘤直径[TTD]）应答，计算了（ΔTTD）变化率，并评估了安全性。200mg 组和 300mg 组的 ORR 分别为 12.5%和 13.33%（ = 1.000）。300mg 组的中位 PFS 长于 200mg 组，但差异无统计学意义（14.98 个月 vs. 9.44 个月）（ = 0.351）。与 200mg 组相比，300mg 组有更多的肿瘤退缩趋势（平均 ΔTTD 率-0.52 ± 0.71 毫米/月 vs. -0.04 ± 1.55 毫米/月， = 0.103）。两组中大多数治疗相关不良事件（AE）均为 1-2 级。两组中最常见的 3 级治疗相关 AE 均为手足皮肤反应和高血压；200mg 组和 300mg 组这两种 AE 的总发生率分别为 11.43%和 22.86%。多纳非尼总体耐受性良好。在局部晚期或转移性 RAIR-DTC 中，两种多纳非尼方案的 ORR 相当。结果提示多纳非尼可能成为 RAIR-DTC 患者的一种新的可行治疗选择，值得进一步研究。临床试验注册：NCT02870569；CTR20160220。
