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帕博西尼与来曲唑治疗晚期乳腺癌的研究
Palbociclib and Letrozole in Advanced Breast Cancer


Richard S. Finn ... 肿瘤 • 2016.11.17
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• CDK4/6新辅助抑制疗法治疗ER阳性乳腺癌

帕博西尼联合来曲唑治疗进展期乳腺癌取得良好疗效

 

姚燕丹

广东省乳腺肿瘤精准诊断和治疗工程研究中心,广东省恶性肿瘤表观遗传与基因调控重点实验室,中山大学孙逸仙纪念医院 

 

激素受体阳性乳腺癌是发病率最高的乳腺癌分子亚型,占乳腺恶性肿瘤的60%~65%。内分泌治疗是激素受体阳性乳腺癌最常用的治疗方法之一。从最早标准的他莫昔芬治疗,到第三代芳香化酶抑制剂的问世,明显改善了激素受体阳性乳腺癌患者的无进展生存期。虽然第三代芳香化酶抑制剂提高了乳腺癌的治疗效果,但仍有部分激素受体阳性乳腺癌患者对此类药物原发耐药。另外,即使对芳香化酶抑制剂初始有效的患者,经过一段时间的治疗后绝大部分患者最终会产生继发耐药。因此,不断探索新的治疗方法仍有必要,联合不同作用靶点及机制的化合物已经从临床前研究逐步过渡到临床研究,有望为乳腺癌患者带来更好的治疗方法。

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摘要


背景

一项二期临床试验表明,在雌激素受体(ER)阳性、人类表皮生长因子受体2型(HER2)阴性的绝经后女性晚期乳腺癌患者中,与来曲唑单药初始治疗相比,帕博西尼(palbociclib)联合来曲唑初始治疗可以延长无进展生存期。我们实施了一项三期临床研究,旨在确认和完善帕博西尼联合来曲唑治疗此类肿瘤的有效性和安全性数据。

 

方法

在这项双盲研究中,共有666例ER阳性、HER2阴性的绝经后女性乳腺癌患者参与,这些患者此前未曾接受过针对晚期疾病的治疗;我们按2∶1的比例将患者随机分组,接受帕博西尼联合来曲唑治疗或安慰剂联合来曲唑治疗。主要终点是由研究者评估的无进展生存期,次要终点包括总生存期、客观缓解、临床获益、患者报告的结局以及药代动力学参数和安全性。

 

结果

帕博西尼联合来曲唑组的中位无进展生存期为24.8个月(95%可信区间[CI],22.1至无法估计),安慰剂联合来曲唑组则为14.5个月(95% CI,12.9~17.1)(疾病进展或死亡的风险比为0.58,95% CI为0.46~0.72,P<0.001)。最常见的3级或4级不良事件包括中性粒细胞减少(帕博西尼联合来曲唑组的发生率为66.4%,安慰剂联合来曲唑组为1.4%)、白细胞减少(24.8%对0%)、贫血(5.4%对1.8%)和疲乏感(1.8%对5%)。在帕博西尼联合来曲唑组中,1.8%的患者报告出现了发热性中性粒细胞减少,安慰剂联合来曲唑组中没有患者报告此不良事件。帕博西尼联合来曲唑组和安慰剂联合来曲唑组分别有43例患者(9.7%)和13例患者(5.9%)因不良事件而永久终止试验药物的治疗。

 

结论

在既往未接受过治疗的ER阳性、HER2阴性晚期乳腺癌患者中,与来曲唑单药治疗相比,帕博西尼联合来曲唑可以显著延长无进展生存期,但骨髓毒性反应的发生比例较高(本项研究由辉瑞公司[Pfizer]资助;PALOMA-2在ClinicalTrials.gov注册号为NCT01740427)





作者信息

Richard S. Finn, M.D., Miguel Martin, M.D., Hope S. Rugo, M.D., Stephen Jones, M.D., Seock-Ah Im, M.D., Ph.D., Karen Gelmon, M.D., Nadia Harbeck, M.D., Ph.D., Oleg N. Lipatov, M.D., Janice M. Walshe, M.D., Stacy Moulder, M.D., Eric Gauthier, Pharm.D., Ph.D., Dongrui R. Lu, M.Sc., Sophia Randolph, M.D., Ph.D., Véronique Diéras, M.D., and Dennis J. Slamon, M.D., Ph.D.
From the Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at the University of California, Los Angeles, Santa Monica (R.S.F., D.J.S.), the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco (H.S.R.), and Pfizer, La Jolla (E.G., D.R.L., S.R.) — all in California; Hospital Gregorio Maranon, Universidad Complutense, Madrid (M.M.); U.S. Oncology Research, The Woodlands, TX (S.J.); Cancer Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); British Columbia Cancer Agency, Vancouver, Canada (K.G.); Brustzentrum der Universität München (LMU), Munich, Germany (N.H.); State Budget Medical Institution Republican Clinical Oncology, Ufa, Russia (O.N.L.); All-Ireland Cooperative Oncology Research Group, Dublin (J.M.W.); M.D. Anderson Cancer Center, University of Texas, Houston (S.M.); and Institut Curie, Paris (V.D.). Address reprint requests to Dr. Finn at the Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at UCLA, 2825 Santa Monica Blvd., Suite 200, Santa Monica, CA 90404, or at rfinn@mednet.ucla.edu.

 

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