背景：在1/2期研究中，作為VEGFR2、MET、AXL和RET抑製劑的卡博紮替尼（C）在放射性碘（RAI）難治性分化型甲狀腺癌（DTC）患者（PT）中顯示出臨床活性（Cabanillas 2017；博澤2018）。這項3期研究（NCT03690388）評估了C組與安慰劑組（P組）在RAI難治性DTC患者中的療效和安全性，這些患者在先前的VEGFR靶向治療期間/之後有進展，但沒有標準的治療。
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：這項雙盲的 III 期試驗納入的患者為接受過包括樂伐替尼或索拉非尼的至多 2 種 VEGFR 抑製劑的 RAI-R DTC 患者，受試者以（ 2:1） [博替尼組（ n=125）和安慰劑組 (n=62)]的比例隨機接受卡博替尼 (60mg,QD)或安慰劑治療，按是否接受過侖伐替尼（是，否）和年齡 (≤65， >65 歲 )來分層。
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.
結果：中位隨訪 6.2 個月，卡博替尼（未達到）相比安慰劑（ 1.9 個月）顯示出明顯的 PFS 改善 (HR0.22,96%CI 0.13 –0.36;p<0.0001) ；在所有預先設定的亞組分析中都觀察到了卡博替尼的獲益，包括是否接受樂伐替尼治療 (是 HR0.26;否 HR0.11)和年齡 (≤65yr,HR0.16;>65yr, HR0.31) 。 ORR 在卡博替尼組和安慰機組分別為 15%和 0%(p=0.0281) ，但不符合預先規定的統計學顯著性標準 (p<0.01) 。同時，也觀察到卡博替尼對安慰劑的 OS 獲益 (HR0.54, 95%CI0.27 –1.11)。治療相關不良事件 (AEs)卡博替尼組均較安慰劑組高，包括腹瀉 (51% vs 3%) 、手足皮膚反應 (46% vs 0%) 、高血壓 (28% vs 5%) 、疲勞 (27% vs 8%) 和惡心 (24% vs 2%) ； 3/4 級 AEs 卡博替尼組有 57%，安慰劑組占 26%。由於 AEs 導致的劑量減少的在卡博替尼組有 57%，安慰劑組隻占 5%，其中卡博替尼組 5%因與疾病進展無關的 AEs 而停止治療，安慰劑組無終止治療情況的發生。兩組均無治療相關死亡的發生。
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.
結論：既往接受過 VEGFR 靶向治療的 RAI-R DTC 患者，卡博替尼相較安慰劑顯示出臨床和統計學上顯著的 PFS 獲益。卡博替尼有望成為既往 VEGFR 靶向治療後進展的 RAI-R DTC 患者的治療標準。
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.
