瑞波西利+非甾体类芳香化酶抑制剂治疗HR+/HER2-早期乳腺癌的安全性与治疗持续时间：一项3期随机对照试验（NATALEE）。
完整摘要 · 中文译文
背景：3期NATALEE试验显示，与单用非甾体芳香化酶抑制剂（NSAI）相比，ribociclib联合NSAI治疗II期或III期HR+/HER2-早期乳腺癌（EBC）患者可带来持续的侵袭性疾病无病生存获益。本文报告NATALEE的详细安全性和耐受性数据，以进一步为临床决策提供信息。 方法：在NATALEE中，患有HR+/HER2- EBC的男性以及绝经前和绝经后女性按1：1随机分配至ribociclib 400 mg/天（用药3周/停药1周；36个月）+ NSAI（阿那曲唑或来曲唑；≥60个月）或单用NSAI。男性和绝经前女性还接受戈舍瑞林。安全性分析包括治疗中出现的不良事件（AE）的发生率以及严重程度、发生时间、管理和结局。还评估了老年与年轻患者之间的安全性参数。 结果：在此45.7个月的中位随访时（数据截止日期：2024年4月29日），安全性分析集包括4967例接受ribociclib + NSAI（n = 2526）或单用NSAI（n = 2441）的患者。ribociclib + NSAI与单用NSAI相比，最常见的≥3级AE分别为中性粒细胞减少（合并术语；44.4% vs. 0.9%）、肝脏相关AE（合并术语；8.6% vs. 1.7%）和白细胞减少（合并术语；8.0% vs. 0.4%）。药物相关严重AE的发生率分别为2.8% vs. 0.5%。在接受ribociclib + NSAI的患者中，因AE停用ribociclib的发生率为20.2%（中位发生时间，4.3个月），其中9.0%因肝脏相关AE而停用。因AE导致ribociclib剂量中断（66.8%；中位发生时间，1.8个月）和 剂量降低（23.0%；中位发生时间，3.2个月）主要由中性粒细胞减少驱动（剂量中断，43.4%；剂量降低，14.1%）。在瑞波西利 + 非甾体芳香化酶抑制剂（NSAI）组中，老年患者（≥ 65岁）与年轻患者（< 65岁）的不良事件（AE）发生率及瑞波西利剂量中断或降低的发生率相似。因AE永久停用瑞波西利的老年患者比例（28.1%；n = 113/402）高于年轻患者（18.6%；n = 396/2124），最常见原因为丙氨酸氨基转移酶升高（老年，8.5%；年轻，7.0%）。 结论：总体而言，瑞波西利 400 mg 耐受性良好，包括在老年患者中，且按照当前NATALEE标签推荐的剂量中断和降低措施，AE可控。试验注册 ClinicalTrials.gov 标识符：NCT03701334（注册日期：2018年9月21日）。
完整摘要 · 英文原文
BACKGROUND: The phase 3 NATALEE trial demonstrated sustained invasive disease-free survival benefit for patients with stage II or III HR+/HER2- early breast cancer (EBC) treated with ribociclib + nonsteroidal aromatase inhibitor (NSAI) vs. NSAI alone. Here we report detailed safety and tolerability data from NATALEE to further inform clinical decision-making. METHODS: In NATALEE, men and pre- and postmenopausal women with HR+/HER2- EBC were randomized 1:1 to ribociclib 400 mg/day (3 weeks on/1 week off; 36 months) + NSAI (anastrozole or letrozole; ≥60 months) or NSAI alone. Men and premenopausal women also received goserelin. Safety analyses included incidence of treatment-emergent adverse events (AEs) as well as severity, timing, management, and outcomes. Safety parameters among older vs. younger patients were also assessed. RESULTS: At this 45.7-month median follow-up (data cutoff: April 29, 2024), the safety analysis set comprised 4967 patients receiving ribociclib + NSAI (n = 2526) or NSAI alone (n = 2441). The most common grade ≥ 3 AEs occurring with ribociclib + NSAI vs. NSAI alone, respectively, were neutropenia (grouped term; 44.4% vs. 0.9%), liver-related AEs (grouped term; 8.6% vs. 1.7%), and leukopenia (grouped term; 8.0% vs. 0.4%). Drug-related serious AEs occurred in 2.8% vs. 0.5%, respectively. Among patients receiving ribociclib + NSAI, AE-related ribociclib discontinuation occurred in 20.2% (median onset, 4.3 months), with 9.0% of instances occurring because of liver-related AEs. AE-related ribociclib dose interruptions (66.8%; median onset, 1.8 months) and dose reductions (23.0%; median onset, 3.2 months) were primarily driven by neutropenia (dose interruptions, 43.4%; dose reductions, 14.1%). In the ribociclib + NSAI arm, AE incidence and ribociclib dose interruptions or reductions occurred at similar rates among older patients (≥ 65 years) and younger patients (< 65 years). A higher proportion of older patients permanently discontinued ribociclib due to AEs (28.1%; n = 113/402) vs. younger patients (18.6%; n = 396/2124), most commonly due to alanine aminotransferase increased (older, 8.5%; younger, 7.0%). CONCLUSIONS: Overall, ribociclib 400 mg was well tolerated, including in older patients, and AEs were manageable with current NATALEE label recommendations of dose interruptions and reductions. Trial registration ClinicalTrials.gov identifier: NCT03701334 (registered September 21, 2018).