Rugo H S, Pritchard K I, Gnant M, Noguchi S, Piccart M, Hortobagyi G, Baselga J, Perez A, Geberth M, Csoszi T, Chouinard E, Srimuninnimit V, Puttawibul P, Eakle J, Feng W, Bauly H, El-Hashimy M, Taran T, Burris H A
University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, USA.
Sunnybrook Odette Cancer Centre and the University of Toronto, Toronto, Canada.
Ann Oncol. 2014 Apr;25(4):808-815. doi: 10.1093/annonc/mdu009. Epub 2014 Mar 10.
In the BOLERO-2 trial, everolimus (EVE), an inhibitor of mammalian target of rapamycin, demonstrated significant clinical benefit with an acceptable safety profile when administered with exemestane (EXE) in postmenopausal women with hormone receptor-positive (HR(+)) advanced breast cancer. We report on the incidence, time course, severity, and resolution of treatment-emergent adverse events (AEs) as well as incidence of dose modifications during the extended follow-up of this study.
Patients were randomized (2:1) to receive EVE 10 mg/day or placebo (PBO), with open-label EXE 25 mg/day (n = 724). The primary end point was progression-free survival. Secondary end points included overall survival, objective response rate, and safety. Safety evaluations included recording of AEs, laboratory values, dose interruptions/adjustments, and study drug discontinuations.
The safety population comprised 720 patients (EVE + EXE, 482; PBO + EXE, 238). The median follow-up was 18 months. Class-effect toxicities, including stomatitis, pneumonitis, and hyperglycemia, were generally of mild or moderate severity and occurred relatively early after treatment initiation (except pneumonitis); incidence tapered off thereafter. EVE dose reduction and interruption (360 and 705 events, respectively) required for AE management were independent of patient age. The median duration of dose interruption was 7 days. Discontinuation of both study drugs because of AEs was higher with EVE + EXE (9%) versus PBO + EXE (3%).
Most EVE-associated AEs occur soon after initiation of therapy, are typically of mild or moderate severity, and are generally manageable with dose reduction and interruption. Discontinuation due to toxicity was uncommon. Understanding the time course of class-effect AEs will help inform preventive and monitoring strategies as well as patient education.
NCT00863655.
在BOLERO - 2试验中，雷帕霉素靶蛋白抑制剂依维莫司（EVE）与依西美坦（EXE）联合应用于激素受体阳性（HR(+)）晚期绝经后乳腺癌女性患者时，显示出显著的临床获益且安全性可接受。我们报告了本研究延长随访期间治疗中出现的不良事件（AE）的发生率、时间进程、严重程度及缓解情况，以及剂量调整的发生率。
患者按2:1随机分组，接受EVE 10mg/天或安慰剂（PBO），同时接受开放标签的EXE 25mg/天（n = 724）。主要终点为无进展生存期。次要终点包括总生存期、客观缓解率和安全性。安全性评估包括记录AE、实验室检查值、剂量中断/调整及研究药物停用情况。
安全人群包括720例患者（EVE + EXE组482例；PBO + EXE组238例）。中位随访时间为18个月。包括口腔炎、肺炎和高血糖在内的类效应毒性一般为轻度或中度，且在治疗开始后相对较早出现（肺炎除外）；此后发生率逐渐下降。因AE管理而进行的EVE剂量减少和中断（分别为360次和705次事件）与患者年龄无关。剂量中断的中位持续时间为7天。因AE而停用两种研究药物的情况在EVE + EXE组（9%）高于PBO + EXE组（3%）。
大多数与EVE相关的AE在治疗开始后不久出现，通常为轻度或中度，一般可通过剂量减少和中断进行管理。因毒性而停药的情况并不常见。了解类效应AE的时间进程将有助于制定预防和监测策略以及患者教育。
NCT00863655。
