The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study
The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study
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DOI：
10.1016/s1470-2045(14)71159-3
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发表时间：
2015-01-01
期刊：
影响因子：
51.1
通讯作者：
Slamon, Dennis J.
中科院分区：
文献类型：
--
作者：
Finn, Richard S.;Crown, John P.;Slamon, Dennis J.
背景Palbociclib（PD-0332991）是一种口服的细胞周期蛋白依赖性激酶（CDK）4和6的小分子抑制剂，临床前证据表明其对雌激素受体阳性乳腺癌细胞具有生长抑制活性，并与抗雌激素药物具有协同作用。我们的目的是评估palbociclib联合来曲唑作为晚期雌激素受体阳性、HER 2阴性乳腺癌患者一线治疗的安全性和有效性。Methods在这项开放标签、随机2期研究中，晚期雌激素受体阳性和HER 2阴性乳腺癌且未接受任何系统性治疗的绝经后女性有资格参加。患者入组两个单独的队列，按顺序进行：在队列1中，仅根据雌激素受体阳性和HER 2阴性生物标志物状态入组患者，而在队列2中，还要求患者患有细胞周期蛋白D1（CCND 1）扩增、p16（INK 4A或CDKN 2A）缺失或两者兼有的癌症。在两个队列中，患者通过基于网络的交互式随机化系统以1：1的比例随机分配，按疾病部位和无病间期分层，接受连续口服来曲唑2.5 mg每日一次或连续口服来曲唑2.5 mg每日一次+口服palbociclib 125 mg，每日一次给药，持续3周，随后停药1周，28天为一个周期。主要终点是意向治疗人群中经评估的无进展生存期。在队列1的计划外中期分析后停止队列2的累积，并将主要终点的统计分析计划修订为队列1和队列2的合并分析（而不是单独的队列2）。该研究正在进行中，但接近入组;这些是无进展生存期的最终分析结果。该研究在ClinicalTrials.gov注册，编号NCT 00721409。结果在2009年12月22日至2012年5月12日期间，我们随机分配了165例患者，84例接受palbociclib+来曲唑治疗，81例接受来曲唑单药治疗。在无进展生存期的最终分析时（palbociclib+来曲唑组的中位随访时间为29.6个月[95% CI 27.9-36.0]，来曲唑组为27.9个月[25.5-31.1]），palbociclib+来曲唑组发生了41例无进展生存期事件，来曲唑组发生了59例。来曲唑组的中位无进展生存期为10.2个月（95% CI 5.7-12.6），palbociclib+来曲唑组为20.2个月（13.8-27.5）（HR 0.488，95% CI 0.319-0.748;单侧p=0.0004）。在队列1（n=66）中，来曲唑组的中位无进展生存期为5.7个月（2.6-10.5），palbociclib+来曲唑组为26.1个月（11.2-无法估计）（HR 0.299，0.156-0.572;单侧p
Background Palbociclib (PD-0332991) is an oral, small-molecule inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 with preclinical evidence of growth-inhibitory activity in oestrogen receptor-positive breast cancer cells and synergy with anti-oestrogens. We aimed to assess the safety and efficacy of palbociclib in combination with letrozole as first-line treatment of patients with advanced, oestrogen receptor-positive, HER2-negative breast cancer.Methods In this open-label, randomised phase 2 study, postmenopausal women with advanced oestrogen receptorpositive and HER2-negative breast cancer who had not received any systemic treatment for their advanced disease were eligible to participate. Patients were enrolled in two separate cohorts that accrued sequentially: in cohort 1, patients were enrolled on the basis of their oestrogen receptor-positive and HER2-negative biomarker status alone, whereas in cohort 2 they were also required to have cancers with amplification of cyclin D1 (CCND1), loss of p16 (INK4A or CDKN2A), or both. In both cohorts, patients were randomly assigned 1: 1 via an interactive web-based randomisation system, stratified by disease site and disease-free interval, to receive continuous oral letrozole 2.5 mg daily or continuous oral letrozole 2.5 mg daily plus oral palbociclib 125 mg, given once daily for 3 weeks followed by 1 week off over 28-day cycles. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Accrual to cohort 2 was stopped after an unplanned interim analysis of cohort 1 and the statistical analysis plan for the primary endpoint was amended to a combined analysis of cohorts 1 and 2 (instead of cohort 2 alone). The study is ongoing but closed to accrual; these are the results of the final analysis of progression-free survival. The study is registered with the ClinicalTrials.gov, number NCT00721409.Findings Between Dec 22, 2009, and May 12, 2012, we randomly assigned 165 patients, 84 to palbociclib plus letrozole and 81 to letrozole alone. At the time of the final analysis for progression-free survival (median follow-up 29.6 months [95% CI 27.9-36.0] for the palbociclib plus letrozole group and 27.9 months [25.5-31.1] for the letrozole group), 41 progression-free survival events had occurred in the palbociclib plus letrozole group and 59 in the letrozole group. Median progression-free survival was 10.2 months (95% CI 5.7-12.6) for the letrozole group and 20.2 months (13.8-27.5) for the palbociclib plus letrozole group (HR 0.488, 95% CI 0.319-0.748; one-sided p=0.0004). In cohort 1 (n=66), median progression-free survival was 5.7 months (2.6-10.5) for the letrozole group and 26.1 months (11.2-not estimable) for the palbociclib plus letrozole group (HR 0.299, 0.156-0.572; one-sided p