背景:Capivasertib是一种有效的,选择性泛AKT抑制剂。在CAPItello-291中,在激素受体阳性/人表皮生长因子受体2阴性的晚期乳腺癌和基于芳香化酶抑制剂的治疗后疾病进展的患者中,与氟维司群单药治疗相比,在无进展生存期中有统计学意义(P<0.001)的改善。CAPItello-291中管理的Capivasertib-氟维司群不良事件(AE)概况的表征可以为未来的管理指导提供信息并优化临床益处。
方法:将78例患者以1:1的比例随机分配至capivasertib(400mg,每天两次;4天,休息3天)或安慰剂,加上富维司坦,4周周期。允许capivasertib/安慰剂的剂量减少/中断(多达两次剂量减少)。安全分析包括暴露,AE,和临床实验室数据,并在接受至少一剂capivasertib的患者中进行,富维司坦,或安慰剂。与磷酸肌醇3-激酶(PI3K)/蛋白激酶(AKT)途径抑制相关的频繁AE(腹泻,皮疹,高血糖)使用组术语进行表征。使用描述性统计对AE进行总结;进行事件发生时间分析。
结果:安全性分析包括705例患者:capivasetib-氟维司群(n=355)和安慰剂-氟维司群(n=350)。常见的任何级别的AEs与capivasertib-氟维司群腹泻(72.4%),皮疹(38.0%),恶心(34.6%);频繁的≥3级AE为皮疹(12.1%),腹泻(9.3%),和高血糖(2.3%)。腹泻,皮疹,和高血糖发生后不久开始capivasertib-氟维司[中位发病天数(四分位数范围)的任何级别:8(2-22),12(10-15),15(1-51)分别],并接受支持性药物治疗,剂量减少,中断,和/或中断。停药率为2.0%,4.5%,0.3%,分别。总的来说,13.0%因不良事件停用Capivasertib。
结论:与PI3K/AKT通路抑制相关的频繁AE发生在早期并且是可控的。治疗中断率低表明,如果管理得当,这些AE不会对临床获益构成挑战.
BACKGROUND: Capivasertib is a potent, selective pan-AKT inhibitor. In CAPItello-291, the addition of capivasertib to fulvestrant resulted in a statistically significant (P < 0.001) improvement in progression-free survival over fulvestrant monotherapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer and disease progression on or after aromatase inhibitor-based therapy. Characterization of the capivasertib-fulvestrant adverse event (AE) profile as managed in CAPItello-291 can inform future management guidance and optimize clinical benefit.
METHODS: Seven hundred and eight patients were randomized 1 : 1 to capivasertib (400 mg twice daily; 4 days on, 3 days off) or placebo, plus fulvestrant, on a 4-week cycle. Dose reductions/interruptions for capivasertib/placebo were permitted (up to two dose reductions). Safety analyses included exposure, AE, and clinical laboratory data and were conducted in patients who received at least one dose of capivasertib, fulvestrant, or placebo. Frequent AEs associated with phosphoinositide 3-kinase (PI3K)/protein kinase (AKT) pathway inhibition (diarrhea, rash, hyperglycemia) were characterized using group terms. AEs were summarized using descriptive statistics; time-to-event analyses were conducted.
RESULTS: Safety analyses included 705 patients: capivasertib-fulvestrant (n = 355) and placebo-fulvestrant (n = 350). Frequent any-grade AEs with capivasertib-fulvestrant were diarrhea (72.4%), rash (38.0%), and nausea (34.6%); frequent grade ≥3 AEs were rash (12.1%), diarrhea (9.3%), and hyperglycemia (2.3%). Diarrhea, rash, and hyperglycemia occurred shortly after starting capivasertib-fulvestrant [median days to onset (interquartile range) of any grade: 8 (2-22), 12 (10-15), and 15 (1-51), respectively], and were managed with supportive medications, dose reductions, interruptions, and/or discontinuation. Discontinuation rates were 2.0%, 4.5%, and 0.3%, respectively. Overall, 13.0% discontinued capivasertib due to AEs.
CONCLUSIONS: Frequent AEs associated with PI3K/AKT pathway inhibition occurred early and were manageable. The low rate of treatment discontinuations suggests that, when appropriately managed, these AEs do not pose a challenge to clinical benefit.