Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial
Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial
复制标题
DOI：
10.1016/s1470-2045(15)00613-0
复制
发表时间：
2016-04-01
期刊：
影响因子：
51.1
通讯作者：
Slamon, Dennis
中科院分区：
文献类型：
--
作者：
Cristofanilli, Massimo;Turner, Nicholas C.;Slamon, Dennis
在PALOMA-3研究中，与氟维司群联合安慰剂相比，CDK 4和CDK 6抑制剂palbociclib联合氟维司群可显著改善转移性乳腺癌患者的无进展生存期。确定最适合在肿瘤复发后将palbociclib添加到内分泌治疗中的患者对于转移性乳腺癌的治疗优化至关重要。我们的目的是证实我们早期的研究结果与此扩展的后续行动，并显示我们的结果，亚组和生物标志物的分析。方法在这个多中心，双盲，随机3期研究，妇女年龄18岁或以上的乳腺癌受体阳性，HER 2阴性转移性乳腺癌，已进展的先前内分泌治疗分层敏感性先前激素治疗，绝经状态，以及在17个国家的144个中心存在内脏转移。符合条件的患者-即，任何绝经状态、东部肿瘤协作组体力状态0-1、仅可测量疾病或骨病、治疗期间或辅助治疗完成后12个月内既往内分泌治疗晚期疾病后疾病复发或进展-被随机分配（2：1）通过集中式交互式网络和语音随机化系统接受口服palbociclib（每日125 mg，持续3周，随后在28天周期内停药一周）加500 mg氟维司群（在周期1的第1天和第15天肌内注射;然后在随后的28天周期的第1天）或安慰剂加氟维司群。主要终点为研究者评估的无进展生存期。我们还通过临床参数、定量受体表达和基线循环DNA中肿瘤PIK 3CA突变状态评估了内分泌治疗抵抗。该研究注册于ClinicalTrials.gov，NCT 01942135。结果在2013年10月7日至2014年8月26日期间，521例患者被随机分配，347例接受氟维司群+哌柏西利，174例接受氟维司群+安慰剂。研究入组已关闭，总生存期随访正在进行中。截至2015年3月16日，共发生259例无进展生存期事件（氟维司群+哌柏西利组145例，氟维司群+安慰剂组114例）;中位随访时间为8.9个月（IQR 8.7-9.2）。氟维司群+哌柏西利组的中位无进展生存期为9.5个月（95% CI 9.2-11.0），氟维司群+安慰剂组为4.6个月（3.5-5.6）（风险比0.46，95% CI 0.36-0.59，p
Background In the PALOMA-3 study, the combination of the CDK4 and CDK6 inhibitor palbociclib and fulvestrant was associated with significant improvements in progression-free survival compared with fulvestrant plus placebo in patients with metastatic breast cancer. Identification of patients most suitable for the addition of palbociclib to endocrine therapy after tumour recurrence is crucial for treatment optimisation in metastatic breast cancer. We aimed to confirm our earlier findings with this extended follow-up and show our results for subgroup and biomarker analyses.Methods In this multicentre, double-blind, randomised phase 3 study, women aged 18 years or older with hormone-receptor-positive, HER2-negative metastatic breast cancer that had progressed on previous endocrine therapy were stratified by sensitivity to previous hormonal therapy, menopausal status, and presence of visceral metastasis at 144 centres in 17 countries. Eligible patients-ie, any menopausal status, Eastern Cooperative Oncology Group performance status 0-1, measurable disease or bone disease only, and disease relapse or progression after previous endocrine therapy for advanced disease during treatment or within 12 months of completion of adjuvant therapy-were randomly assigned (2:1) via a centralised interactive web-based and voice-based randomisation system to receive oral palbociclib (125 mg daily for 3 weeks followed by a week off over 28-day cycles) plus 500 mg fulvestrant (intramuscular injection on days 1 and 15 of cycle 1; then on day 1 of subsequent 28-day cycles) or placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival. Analysis was by intention to treat. We also assessed endocrine therapy resistance by clinical parameters, quantitative hormone-receptor expression, and tumour PIK3CA mutational status in circulating DNA at baseline. This study is registered with ClinicalTrials.gov, NCT01942135.Findings Between Oct 7, 2013, and Aug 26, 2014, 521 patients were randomly assigned, 347 to fulvestrant plus palbociclib and 174 to fulvestrant plus placebo. Study enrolment is closed and overall survival follow-up is in progress. By March 16, 2015, 259 progression-free-survival events had occurred (145 in the fulvestrant plus palbociclib group and 114 in the fulvestrant plus placebo group); median follow-up was 8.9 months (IQR 8.7-9.2). Median progression-free survival was 9.5 months (95% CI 9.2-11.0) in the fulvestrant plus palbociclib group and 4.6 months (3.5-5.6) in the fulvestrant plus placebo group (hazard ratio 0.46, 95% CI 0.36-0.59, p