放射性碘难治性分化甲状腺癌(rir - dtc)患者预后差，治疗选择有限。评估阿帕替尼(一种高选择性血管内皮生长因子(VEGFR-2)抑制剂)在进展性局部晚期或转移性RAIR-DTC患者中的疗效和安全性。

这项随机、双盲、安慰剂对照、三期试验(Apatinib在放射性碘难治性分化型甲状腺癌中的疗效[REALITY])于2017年2月17日至2020年3月2日期间在中国21个试验点的92例进展性局部晚期或转移性rir - dtc患者中进行，分析数据截止日期为2020年3月25日。患者被随机分配(1:1)服用阿帕替尼、500 mg/d或安慰剂。在接受安慰剂时病情进展的患者被允许转用阿帕替尼。主要终点为研究者评估的无进展生存期(PFS)。次要终点包括总生存率、客观缓解率(ORR)、疾病控制率(DCR)、缓解时间、客观缓解时间和安全性。进行意向治疗分析以评估疗效。

在纳入试验的92例患者中，56例为女性(60.9%);基线时的平均(SD)年龄为55.7(10.6)岁。患者被随机分为阿帕替尼组(n = 46)和安慰剂组(n = 46)。中位随访时间为18.1个月(IQR为12.7-22.2个月)。阿帕替尼的中位PFS为22.2个月(95% CI, 10.91-未达到)，安慰剂为4.5个月(95% CI, 1.94-9.17)(风险比，0.26;95%置信区间,0.14 - -0.47;P & lt;措施)。阿帕替尼组的确诊ORR为54.3% (95% CI, 39.0% ~ 69.1%)， DCR为95.7% (95% CI, 85.2% ~ 99.5%)，而安慰剂组的ORR为2.2% (95% CI, 0.1% ~ 11.5%)， DCR为58.7% (95% CI, 43.2% ~ 73.0%)。阿帕替尼的中位总生存期未达到(95% CI, 26.25未达到)，安慰剂的中位总生存期为29.9个月(95% CI, 18.96-未达到)(风险比，0.42;95%置信区间,0.18 - -0.97;P = .04点)。阿帕替尼组中最常见的3级或更高级别治疗相关不良事件为高血压(16例[34.8%])、手足综合征(8例[17.4%])、蛋白尿(7例[15.2%])和腹泻(7例[15.2%])，而安慰剂组中没有发生这些不良事件。在预先指定的中期分析中，REALITY试验满足了其PFS的主要终点。在进展性局部晚期或转移性RAIR-DTC患者中，阿帕替尼在延长PFS和总生存期方面均显示出显著的临床益处，且安全性可控。

Abstract

Importance: Patients with radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) have a poor prognosis and limited treatment options.

Objective: To assess the efficacy and safety of apatinib, a highly selective vascular endothelial growth factor (VEGFR-2) inhibitor, in patients with progressive locally advanced or metastatic RAIR-DTC.

Design, setting, and participants: This randomized, double-blind, placebo-controlled, phase 3 trial (Efficacy of Apatinib in Radioactive Iodine-refractory Differentiated Thyroid Cancer [REALITY]) was conducted in 92 patients with progressive locally advanced or metastatic RAIR-DTC between February 17, 2017, and March 2, 2020, at 21 sites within China, and the data cutoff date for this analysis was March 25, 2020.

Interventions: Patients were randomly assigned (1:1) to apatinib, 500 mg/d, or placebo. Patients who developed progression while receiving placebo were allowed to cross over to apatinib.

Main outcomes and measures: The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival, objective response rate (ORR), disease control rate (DCR), duration of response, time to objective response, and safety. Intention-to-treat analyses were performed to evaluate efficacy.

Results: Of the 92 patients included in the trial, 56 were women (60.9%); mean (SD) age at baseline was 55.7 (10.6) years. Patients were randomized to the apatinib (n = 46) or placebo (n = 46) group. The median follow-up duration was 18.1 (IQR, 12.7-22.2) months. The median PFS was 22.2 (95% CI, 10.91-not reached) months for apatinib vs 4.5 (95% CI, 1.94-9.17) months for placebo (hazard ratio, 0.26; 95% CI, 0.14-0.47; P < .001). The confirmed ORR was 54.3% (95% CI, 39.0%-69.1%) and the DCR was 95.7% (95% CI, 85.2%-99.5%) in the apatinib group vs an ORR of 2.2% (95% CI, 0.1%-11.5%) and DCR of 58.7% (95% CI, 43.2%-73.0%) in the placebo group. The median overall survival was not reached for apatinib (95% CI, 26.25-not reached) and was 29.9 months (95% CI, 18.96-not reached) for placebo (hazard ratio, 0.42; 95% CI, 0.18-0.97; P = .04). The most common grade 3 or higher-level treatment-related adverse events in the apatinib group were hypertension (16 [34.8%]), hand-foot syndrome (8 [17.4%]), proteinuria (7 [15.2%]), and diarrhea (7 [15.2%])-none of which occurred in the placebo group.

Conclusions and relevance: The REALITY trial met its primary end point of PFS at the prespecified interim analysis. Apatinib showed significant clinical benefits in both prolonged PFS and overall survival with a manageable safety profile in patients with progressive locally advanced or metastatic RAIR-DTC.

原文链接

pubmed.ncbi.nlm.nih.gov/34913959/

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