CHU Sart Tilman Liege and Liege University, Liege, Belgium.
Royal Melbourne Hospital, Victoria, Australia.
JAMA Oncol. 2018 Oct 1;4(10):1367-1374. doi: 10.1001/jamaoncol.2018.2262.
Everolimus plus exemestane and capecitabine are approved second-line therapies for advanced breast cancer.
A postapproval commitment to health authorities to estimate the clinical benefit of everolimus plus exemestane vs everolimus or capecitabine monotherapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer.
Open-label, randomized, phase 2 trial of treatment effects in postmenopausal women with advanced breast cancer that had progressed during treatment with nonsteroidal aromatase inhibitors.
Patients were randomized to 3 treatment regimens: (1) everolimus (10 mg/d) plus exemestane (25 mg/d); (2) everolimus alone (10 mg/d); and (3) capecitabine alone (1250 mg/m2 twice daily).
Estimated hazard ratios (HRs) of progression-free survival (PFS) for everolimus plus exemestane vs everolimus alone (primary objective) or capecitabine alone (key secondary objective). Safety was a secondary objective. No formal statistical comparisons were planned.
A total of 309 postmenopausal women were enrolled, median age, 61 years (range, 32-88 years). Of these, 104 received everolimus plus exemestane; 103, everolimus alone; and 102, capecitabine alone. Median follow-up from randomization to the analysis cutoff (June 1, 2017) was 37.6 months. Estimated HR of PFS was 0.74 (90% CI, 0.57-0.97) for the primary objective of everolimus plus exemestane vs everolimus alone and 1.26 (90% CI, 0.96-1.66) for everolimus plus exemestane vs capecitabine alone. Between treatment arms, potential informative censoring was noted, and a stratified multivariate Cox regression model was used to account for imbalances in baseline characteristics; a consistent HR was observed for everolimus plus exemestane vs everolimus (0.73; 90% CI, 0.56-0.97), but the HR was closer to 1 for everolimus plus exemestane vs capecitabine (1.15; 90% CI, 0.86-1.52). Grade 3 to 4 adverse events were more frequent with capecitabine (74%; n = 75) vs everolimus plus exemestane (70%; n = 73) or everolimus alone (59%; n = 61). Serious adverse events were more frequent with everolimus plus exemestane (36%; n = 37) vs everolimus alone (29%; n = 30) or capecitabine (29%; n = 30).
These findings suggest that everolimus plus exemestane combination therapy offers a PFS benefit vs everolimus alone, and they support continued use of this therapy in this setting. A numerical PFS difference with capecitabine vs everolimus plus exemestane should be interpreted cautiously owing to imbalances among baseline characteristics and potential informative censoring.
ClinicalTrials.gov identifier: NCT01783444.
依维莫司联合依西美坦和卡培他滨是晚期乳腺癌二线治疗的标准方案。
向卫生当局提交一项批准后的承诺，以评估依维莫司联合依西美坦对比依维莫司或卡培他滨单药治疗雌激素受体阳性、人表皮生长因子受体 2 阴性晚期乳腺癌的临床获益。
这是一项在接受非甾体芳香化酶抑制剂治疗后进展的绝经后晚期乳腺癌女性中进行的治疗效果的开放性标签、随机、2 期临床试验。
患者被随机分为 3 种治疗方案：（1）依维莫司（10mg/d）联合依西美坦（25mg/d）；（2）依维莫司单药（10mg/d）；和（3）卡培他滨单药（1250mg/m2，每日 2 次）。
依维莫司联合依西美坦对比依维莫司单药（主要终点）或卡培他滨单药（关键次要终点）的无进展生存期（PFS）的估计风险比（HR）。安全性是次要终点。没有计划进行正式的统计学比较。
共纳入 309 例绝经后女性，中位年龄为 61 岁（范围为 32-88 岁）。其中，104 例接受了依维莫司联合依西美坦治疗；103 例接受了依维莫司单药治疗；102 例接受了卡培他滨单药治疗。自随机分组至分析截止日期（2017 年 6 月 1 日）的中位随访时间为 37.6 个月。主要终点为依维莫司联合依西美坦对比依维莫司单药的 PFS 的估计 HR 为 0.74（90%CI，0.57-0.97），而依维莫司联合依西美坦对比卡培他滨单药的 HR 为 1.26（90%CI，0.96-1.66）。在治疗组之间，注意到潜在的信息性删失，因此使用分层多变量 Cox 回归模型来解释基线特征的不平衡；对于依维莫司联合依西美坦对比依维莫司的 HR 观察到一致的结果（0.73；90%CI，0.56-0.97），但依维莫司联合依西美坦对比卡培他滨的 HR 更接近 1（1.15；90%CI，0.86-1.52）。卡培他滨（74%；n=75）比依维莫司联合依西美坦（70%；n=73）或依维莫司单药（59%；n=61）更常出现 3 级或 4 级不良事件。依维莫司联合依西美坦（36%；n=37）比依维莫司单药（29%；n=30）或卡培他滨（29%；n=30）更常发生严重不良事件。
这些发现表明，依维莫司联合依西美坦联合治疗与依维莫司单药治疗相比可带来 PFS 获益，支持在该治疗环境中继续使用该疗法。与依维莫司联合依西美坦相比，卡培他滨的 PFS 差异应谨慎解释，因为存在基线特征的不平衡和潜在的信息性删失。
ClinicalTrials.gov 标识符：NCT01783444。
