German Breast Group GBG Forschungs GmbH, Neu-Isenburg, Germany
Centre for Haematology and Oncology Bethanien, Frankfurt, Germany.
Oncologist. 2017 Sep;22(9):1028-1038. doi: 10.1634/theoncologist.2017-0072. Epub 2017 Jun 26.
The efficacy and safety of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, combined with fulvestrant and goserelin was assessed in premenopausal women with advanced breast cancer (ABC) who had progressed on prior endocrine therapy (ET).
One hundred eight premenopausal endocrine-refractory women ≥18 years with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) ABC were among 521 women randomized 2:1 (347:174) to fulvestrant (500 mg) ± goserelin with either palbociclib (125 mg/day orally, 3 weeks on, 1 week off) or placebo. This analysis assessed whether the overall tolerable safety profile and significant progression-free survival (PFS) improvement extended to premenopausal women. Potential drug-drug interactions (DDIs) and ovarian suppression with goserelin were assessed via plasma pharmacokinetics and biochemical analyses, respectively. (ClinicalTrials.gov identifier: NCT01942135) RESULTS: Median PFS for premenopausal women in the palbociclib ( = 72) versus placebo arm ( = 36) was 9.5 versus 5.6 months, respectively (hazard ratio, 0.50, 95% confidence interval: 0.29-0.87), and consistent with the significant PFS improvement in the same arms for postmenopausal women. Any-grade and grade ≤3 neutropenia, leukopenia, and infections were among the most frequent adverse events reported in the palbociclib arm with concurrent goserelin administration. Hormone concentrations were similar between treatment arms and confirmed sustained ovarian suppression. Clinically relevant DDIs were not observed.
Palbociclib combined with fulvestrant and goserelin was an effective and well-tolerated treatment for premenopausal women with prior endocrine-resistant HR+/HER2- ABC. Inclusion of both premenopausal and postmenopausal women in pivotal combination ET trials facilitates access to novel drugs for young women and should be considered as a new standard for clinical trial design.
PALOMA-3, the first registrational study to include premenopausal women in a trial investigating a CDK4/6 inhibitor combined with endocrine therapy, has the largest premenopausal cohort reported in an endocrine-resistant setting. In pretreated premenopausal women with hormone receptor-positive advanced breast cancer, palbociclib plus fulvestrant and goserelin (luteinizing hormone-releasing hormone [LHRH] agonist) treatment almost doubled median progression-free survival (PFS) and significantly increased the objective response rate versus endocrine monotherapy, achieving results comparable to those reported for chemotherapy without apparently interfering with LHRH agonist-induced ovarian suppression. The significant PFS gain and tolerable safety profile strongly support use of this regimen in premenopausal women with endocrine-resistant disease who could possibly delay chemotherapy.
在先前内分泌治疗（ET）进展的绝经前激素受体阳性（HR+）/人表皮生长因子受体 2 阴性（HER2-）晚期乳腺癌（ABC）患者中，评估了细胞周期蛋白依赖性激酶 4/6 抑制剂帕博西利与氟维司群和戈舍瑞林联合应用的疗效和安全性。
共有 521 名女性随机分为 2:1（347:174）接受氟维司群（500mg）±戈舍瑞林治疗，其中 108 名绝经前内分泌难治性 HR+/HER2-ABC 患者年龄均≥18 岁。本分析评估了整体可耐受的安全性概况和显著的无进展生存期（PFS）改善是否扩展到绝经前妇女。通过血浆药代动力学和生化分析分别评估了潜在的药物-药物相互作用（DDI）和戈舍瑞林的卵巢抑制作用。（临床试验标识符：NCT01942135）
帕博西利（ = 72）与安慰剂（ = 36）组绝经前妇女的中位 PFS 分别为 9.5 个月和 5.6 个月（风险比，0.50，95%置信区间：0.29-0.87），与绝经后妇女相同手臂中显著的 PFS 改善一致。中性粒细胞减少症、白细胞减少症和感染等任何级别和≤3 级不良事件是接受帕博西利联合戈舍瑞林治疗的最常见不良事件。治疗组之间的激素浓度相似，证实了持续的卵巢抑制。未观察到临床相关的 DDI。
帕博西利联合氟维司群和戈舍瑞林是一种有效且耐受良好的治疗方法，适用于先前内分泌耐药的 HR+/HER2-ABC 的绝经前妇女。在关键性联合 ET 试验中纳入绝经前和绝经后妇女，为年轻女性获得新型药物提供了便利，应被视为临床试验设计的新标准。
PALOMA-3 是第一项在包括绝经前妇女的试验中评估 CDK4/6 抑制剂联合内分泌治疗的注册研究，报告了内分泌耐药环境中最大的绝经前队列。在激素受体阳性的晚期乳腺癌中，接受预处理的绝经前妇女中，与内分泌单药治疗相比，帕博西利加氟维司群和戈舍瑞林（促黄体激素释放激素 [LHRH] 激动剂）治疗使中位无进展生存期（PFS）几乎翻了一番，并显著提高了客观缓解率，结果与化疗报告的结果相当，而不会明显干扰 LHRH 激动剂诱导的卵巢抑制。显著的 PFS 获益和可耐受的安全性概况强烈支持在可能需要延迟化疗的内分泌耐药疾病的绝经前妇女中使用该方案。
