肿瘤

卡博替尼在放射性碘难治性甲状腺癌患者中显示疗效:III 期 COSMIC-311 试验结果

作者:会飞的大胖纸 来源:医学论坛网 日期:2021-06-30
导读

         背景:在1/2期研究中,作为VEGFR2、MET、AXL和RET抑制剂的卡博扎替尼(C)在放射性碘(RAI)难治性分化型甲状腺癌(DTC)患者(PT)中显示出临床活性(Cabanillas 2017;博泽2018)。这项3期研究(NCT03690388)评估了C组与安慰剂组(P组)在RAI难治性DTC患者中的疗效和安全性,这些患者在先前的VEGFR靶向治疗期间/之后有进展,但没有标准的治疗。

关键字:  肿瘤 

背景:在1/2期研究中,作为VEGFR2、MET、AXL和RET抑制剂的卡博扎替尼(C)在放射性碘(RAI)难治性分化型甲状腺癌(DTC)患者(PT)中显示出临床活性(Cabanillas 2017;博泽2018)。这项3期研究(NCT03690388)评估了C组与安慰剂组(P组)在RAI难治性DTC患者中的疗效和安全性,这些患者在先前的VEGFR靶向治疗期间/之后有进展,但没有标准的治疗。

 

Background: Cabozantinib (C), an inhibitor of VEGFR2, MET, AXL, and RET, showed clinical activity in patients (pts) with radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) in phase 1/2 studies (Cabanillas 2017; Brose 2018). This phase 3 study (NCT03690388) evaluated the efficacy and safety of C vs placebo (P) in pts with RAI-refractory DTC who had progressed during/after prior VEGFR-targeted therapy for whom there is no standard of care.

 

方法:这项双盲的 III 期试验纳入的患者为接受过包括乐伐替尼或索拉非尼的至多 2 种 VEGFR 抑制剂的 RAI-R DTC 患者,受试者以( 2:1) [博替尼组( n=125)和安慰剂组 (n=62)]的比例随机接受卡博替尼 (60mg,QD)或安慰剂治疗,按是否接受过仑伐替尼(是,否)和年龄 (≤65, >65 岁 )来分层。

 

Methods: In this double-blind, phase 3 trial, pts were randomized 2:1 to receive C (60 mg QD) or P, stratified by prior lenvatinib treatment (L; yes, no) and age (≤65, > 65 yr). Pts with RAI-refractory DTC must have received L or sorafenib for DTC and progressed during or following treatment with ≤ 2 prior VEGFR inhibitors. Pts randomized to P could cross over to open-label C upon disease progression per blinded independent radiology committee (BIRC). The primary endpoints were objective response rate (ORR) in the first 100 randomized pts and progression-free survival (PFS) in all randomized pts. PFS and ORR were assessed by BIRC per RECIST v1.1. The study was designed to detect an ORR for C vs P (2-sided α = 0.01) and a hazard ratio (HR) for PFS of 0.61 (90% power, 2-sided α = 0.04). A prespecified interim PFS analysis was planned for the ITT population at the time of the primary ORR analysis.

 

结果:中位随访 6.2 个月,卡博替尼(未达到)相比安慰剂( 1.9 个月)显示出明显的 PFS 改善 (HR0.22,96%CI 0.13 –0.36;p<0.0001) ;在所有预先设定的亚组分析中都观察到了卡博替尼的获益,包括是否接受乐伐替尼治疗 (是 HR0.26;否 HR0.11)和年龄 (≤65yr,HR0.16;>65yr, HR0.31) 。 ORR 在卡博替尼组和安慰机组分别为 15%和 0%(p=0.0281) ,但不符合预先规定的统计学显著性标准 (p<0.01) 。同时,也观察到卡博替尼对安慰剂的 OS 获益 (HR0.54, 95%CI0.27 –1.11)。治疗相关不良事件 (AEs)卡博替尼组均较安慰剂组高,包括腹泻 (51% vs 3%) 、手足皮肤反应 (46% vs 0%) 、高血压 (28% vs 5%) 、疲劳 (27% vs 8%) 和恶心 (24% vs 2%) ; 3/4 级 AEs 卡博替尼组有 57%,安慰剂组占 26%。由于 AEs 导致的剂量减少的在卡博替尼组有 57%,安慰剂组只占 5%,其中卡博替尼组  5%因与疾病进展无关的 AEs 而停止治疗,安慰剂组无终止治疗情况的发生。两组均无治疗相关死亡的发生。

 

Results: As of 19 Aug 2020,125 vs 62 pts had been randomized to the C and P arms, respectively; median age was 66 yr, 55% were female and 63% received prior L. Median (m) follow-up was 6.2 months (mo). At the planned interim analysis, the trial met the primary endpoint of PFS with C demonstrating significant improvement over P (HR 0.22, 96% CI 0.13–0.36; p < 0.0001). mPFS was not reached for C vs 1.9 mo for P; PFS benefit was observed in all prespecified subgroups including prior L (yes, HR 0.26; no, HR 0.11) and age (≤65 yr, HR 0.16; > 65 yr, HR 0.31). ORR was 15% for C vs 0% for P (p = 0.0281) but did not meet the prespecified criteria for statistical significance (p < 0.01). A favorable OS trend was observed for C vs P (HR 0.54, 95% CI 0.27–1.11). Treatment-emergent adverse events (AEs) of any grade with higher occurrences in the C vs P arm included diarrhea (51% vs 3%), hand-foot skin reaction (46% vs 0%), hypertension (28% vs 5%), fatigue (27% vs 8%), and nausea (24% vs 2%); grade 3/4 AEs were experienced by 57% of pts with C vs 26% with P. Dose reductions due to any grade AEs occurred in 57% of pts with C vs 5% with P. Treatment discontinuations due to AEs not related to disease progression occurred in 5% of pts with C vs 0% with P. No treatment-related deaths occurred in either arm.

 

结论:既往接受过 VEGFR 靶向治疗的 RAI-R DTC 患者,卡博替尼相较安慰剂显示出临床和统计学上显著的 PFS 获益。卡博替尼有望成为既往 VEGFR 靶向治疗后进展的 RAI-R DTC 患者的治疗标准。

 

Conclusions: C showed a clinically and statistically significant improvement in PFS over P in pts with RAI-refractory DTC after prior VEGFR-targeted therapy with no unexpected toxicities. C may represent a new standard of care in pts with previously treated DTC.

 

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