来源：肿瘤资讯
PALOMA-2: 一项palbociclib（P）联合来曲唑（L）对照来曲唑治疗绝经后ER+/HER2–晚期女性乳腺癌（ABC）的III期研究主要结果
摘要编号：507
Citation: J Clin Oncol 34, 2016 (suppl; abstr 507)
背景：激素治疗（HT）是ER+乳腺癌患者的主要治疗方式。palbociclib是一种细胞周期依赖性激酶抑制剂，在临床前模型中显示阻断ER+/HER2-乳腺癌生长。PALOMA-1在一项开放标签II期临床研究中，证实在L的基础上增加P一线治疗ER+/HER2-晚期乳腺癌患者，有可耐受的安全性，且显著改善PFS (20.2 月比10.2 月)，据此获得了FDA的加速审批。PALOMA-2为一项随机对照、双盲的III期的研究，以验证如上结果。
方法：研究纳入666例绝经后既往未接受针对晚期系统性治疗的乳腺癌患者，按2：1随机分配至P（口服 125 mg/d; 连续服药3周休1周）+L（2.5 mg/d 每日口服）或安慰剂+L，28天一疗程，直至疾病进展，撤回知情同意或死亡。患者按病灶部位，（新）辅助结束后无病间期，既往激素治疗（有/无）进行分层。主要研究终点：研究者评估PFS，关键次要终点：总生存（OS），客观缓解率（ORR），临床获益率（CBR=CR+PR+SD≥24周），患者报告结果和安全性。疗效评估12周一次，统计学估计，P＋L组要达到HR ≤0.69需要的终点事件数为347例（90%检验效能，单侧α=0.025）。
结果：至2016年2月26日，共发生331例PFS事件。两组基线特征相似。中位PFS为24.8月（P+L）比14.5月（安慰剂+L）(HR=0.58 [0.46–0.72], P<0.000001)。P+L组改善ORR（42.1%比34.7%, P=0.031; 可测量病灶者55.3%比44.4% [P=0.013]）。最常见不良反应（AEs ，所有级别）P+L组比安慰剂+L组为：中性粒细胞减少(79.5% vs 6.3%)，乏力(37.4% vs 27.5%)，恶心(35.1% vs 26.1%)，关节痛(33.3%比33.8%)，脱发(32.9% vs 15.8%)。最常见不良事件为严重的G3中性粒细胞减少(56.1%)及其他G1的不良事件。发热性中性粒细胞减少见于P+L组（2.5%）。因不良事件导致永久终止治疗的发生率为9.7%（P+L）比5.9%（安慰剂+L）。OS数据尚未成熟，待进一步分析。
结论：PALOMA-2研究在扩大的人群中证实了P+L治疗未经针对晚期疾病系统性治疗的ER+/HER2-晚期乳腺癌的显著疗效。临床研究信息：NCT01740427
PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2– advanced breast cancer (ABC).
Abstract No:507
Abstract:
Background: Hormonal therapy (HT) is the mainstay for patients (pts) with ER+ BC. P, a cyclin-dependent kinase 4/6 inhibitor, blocks growth of ER+/HER2– BC preclinical models. In PALOMA-1, an open-label Ph 2 trial, addition of P to L improved median PFS vs L alone (20.2 months [mo] vs 10.2 mo) in pts with first-line ER+/HER2– ABC with acceptable safety, leading to accelerated FDA approval. PALOMA-2 is a randomized double-blind Ph 3 trial designed to confirm these results.
Methods: 666 postmenopausal pts with no prior systemic therapy for ABC were randomized 2:1 to receive P (oral 125 mg/d; 3 wks on/1 wk off) + L (2.5 mg/d continuously) or PLB + L every 28 days until disease progression, consent withdrawal or death. Pts were stratified by disease site, disease-free interval from end of (neo)adjuvant therapy, and prior HT (yes/no). Primary endpoint: investigator-assessed PFS; key secondary endpoints: overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR=CR + PR + SD ≥24 wks), patient-reported outcomes and safety. Tumor assessments were every 12 wks. 347 events were needed with 90% power to detect a hazard ratio (HR) ≤0.69 in favor of P+L (1-sided α=0.025).
Results: By 26 Feb 2016, 331 PFS events occurred. Baseline characteristics were well balanced. Median PFS was 24.8 mo (P+L) vs 14.5 mo (PLB+L) (HR=0.58 [0.46–0.72], P<0.000001). ORR was improved with P+L (42.1% vs 34.7%, P=0.031; 55.3% vs 44.4% in pts with measurable disease [P=0.013]). CBR was 84.9% vs 70.3% (P<.0001). Common adverse events (AEs; all grades) with P+L vs PLB+L were neutropenia (79.5% vs 6.3%), fatigue (37.4% vs 27.5%), nausea (35.1% vs 26.1%), arthralgia (33.3% vs 33.8%) and alopecia (32.9% vs 15.8%). Most common severity seen was G3 for neutropenia (56.1%) and G1 for the other AEs. Febrile neutropenia was seen only with P+L (2.5%). Permanent discontinuation due to AEs was 9.7% (P+L) vs 5.9% (PLB+L). OS data are immature; final OS analysis is pending.
Conclusion: PALOMA-2 expands and confirms the significant clinical benefit and safety of P+L in ER+/HER2– ABC pts who had not received prior systemic therapy for their advanced disease. Clinical trial information: NCT01740427
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