绝经后晚期乳腺癌的蒙娜利莎疗法
编者按：利泊昔布（利波西利、瑞波西利、LEE011）属于细胞周期蛋白依赖型激酶4和6（CDK4/6）抑制剂，可以阻断乳腺癌细胞有丝分裂周期由DNA合成前期（G1期）进入DNA合成期（S期）。2016年，MONALEESA-2研究结果表明，利泊昔布＋来曲唑（雌激素非甾体类芳香酶抑制剂）与单用来曲唑相比，一线治疗绝经后激素受体阳性HER2阴性晚期乳腺癌患者的无进展生存显著改善。那么，利泊昔布＋氟维司群（选择性雌激素受体抑制剂）与单用氟维司群相比，治疗绝经后激素受体阳性HER2阴性晚期乳腺癌患者的效果如何？
2018年6月3日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表洛杉矶加利福尼亚大学医学中心、纽约大学朗格尼医学中心、阿肯色州费耶特维尔乳腺癌研究中心、比利时鲁汶大学医院、列日大学中心医院、加拿大不列颠哥伦比亚癌症中心、德国埃尔朗根纽伦堡大学医院、费尔贝特肿瘤医院、意大利那不勒斯肿瘤研究所、米兰肿瘤研究所、韩国首尔大学医院、捷克马萨里克纪念癌症研究所、西班牙乳腺癌研究协作组、马德里大学、癌症网络生物医学研究中心、格雷戈里奥·马拉尼翁卫生研究所、塞维利亚大学马卡丽娜圣女医院、荷兰癌症研究所乳腺癌研究协作组研究中心、法国斯特拉斯堡癌症研究所、美国诺华、瑞士诺华的III期随机对照临床研究（MONALEESA-3）报告，探讨了氟维司群±利泊昔布一线或二线治疗绝经后激素受体阳性HER2阴性晚期乳腺癌患者的有效性和安全性。
MONALEESA-1: A Pharmacodynamics Pre-surgical Study of LEE011 in Early Breast Cancer Patients.
MONALEESA-2: Study of Efficacy and Safety of LEE011 in Postmenopausal Women With Advanced Breast Cancer.
MONALEESA-3: Study of Efficacy and Safety of LEE011 in Men and Postmenopausal Women With Advanced Breast Cancer.
MONALEESA-7: Study of Efficacy and Safety in Premenopausal Women With Hormone Receptor Positive, HER2-negative Advanced Breast Cancer
该III期随机对照临床研究（MONALEESA-3）于2015年6月～2016年6月从27个国家177家医院入组激素受体阳性、HER2阴性晚期乳腺癌未经治疗或既往一线内分泌治疗失败的绝经后女性患者726例，按2∶1的比例随机分配接受利泊昔布＋氟维司群（484例）或安慰剂＋氟维司群（242例）。主要研究终点由当地评定无进展生存。次要研究终点包括总生存、总有效率、安全性。
结果发现，利泊昔布＋氟维司群与安慰剂＋氟维司群相比：
中位无进展生存显著延长7.7个月（20.5比12.8，95%置信区间：18.5～23.5、10.9～16.3）
复发或死亡风险显著减少40.7%（风险比：0.593，95%置信区间：0.480～0.732，P<0.001）
一线治疗与二线治疗的效果相似：
一线治疗使风险显著减少42.3%（风险比：0.577，95%置信区间：0.415～0.802）
二线治疗使风险显著减少43.5%（风险比：0.565，95%置信区间：0.428～0.744）
对于可测量病变患者，利泊昔布＋氟维司群与安慰剂＋氟维司群相比，总有效率较高（40.9%比28.7%）。
利泊昔布＋氟维司群与安慰剂＋氟维司群相比，报告发生率≥10%的3级不良事件和≥5%的4级不良事件：
3级中性粒细胞减少：46.6%比0%
3级白细胞减少：13.5%比0%
4级中性粒细胞减少：6.8%比0%
因此，该研究结果表明，利泊昔布＋氟维司群可以作为激素受体阳性、HER2阴性晚期乳腺癌的一线或二线治疗选择。
相关阅读
J Clin Oncol. 2018 Jun 3. [Epub ahead of print]
Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3.
Dennis J. Slamon, Patrick Neven, Stephen Chia, Peter A. Fasching, Michelino De Laurentiis, Seock-Ah Im, Katarina Petrakova, Giulia Val Bianchi, Francisco J. Esteva, Miguel Martín, Arnd Nusch, Gabe S. Sonke, Luis De la Cruz-Merino, J. Thaddeus Beck, Xavier Pivot, Gena Vidam, Yingbo Wang, Karen Rodriguez Lorenc, Michelle Miller, Tetiana Taran, Guy Jerusalem.
University of California Los Angeles Medical Center, Santa Monica, CA; Universitair Ziekenhuis, Leuven; Centre Hospitalier Universitaire de Liege and Liege University, Liège, Belgium; British Columbia Cancer Agency, Vancouver, British Columbia, Canada; University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen; Practice for Hematology and Internal Oncology, Velbert, Germany; Istituto Nazionale Tumori, Fondazione G. Pascale, Naples; Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy; Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; Masaryk Memorial Cancer Institute, Brno, Czech Republic; New York University Langone Health, New York, NY; Instituto de Investigacion Sanitaria Gregorio Maranon, Centro de Investigación Biomédica en Red de Cáncer, Grupo Espanol de Investigación en Cáncer de Mama, Universidad Complutense, Madrid; Hospital Universitario Virgen Macarena, Seville, Spain; Netherlands Cancer Institute / Borstkanker Onderzoek Groep Study Center, Amsterdam, the Netherlands; Highlands Oncology Group, Fayetteville, AR; Institut Régional du Cancer, Strasbourg, France; Novartis Pharmaceuticals, East Hanover, NJ; Novartis Pharma, Basel, Switzerland.
PURPOSE: This phase III study evaluated ribociclib plus fulvestrant in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer who were treatment naive or had received up to one line of prior endocrine therapy in the advanced setting.
PATIENTS AND METHODS: Patients were randomly assigned at a two-to-one ratio to ribociclib plus fulvestrant or placebo plus fulvestrant. The primary end point was locally assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety.
RESULTS: A total of 484 postmenopausal women were randomly assigned to ribociclib plus fulvestrant, and 242 were assigned to placebo plus fulvestrant. Median progression-free survival was significantly improved with ribociclib plus fulvestrant versus placebo plus fulvestrant: 20.5 months (95% CI, 18.5 to 23.5 months) versus 12.8 months (95% CI, 10.9 to 16.3 months), respectively (hazard ratio, 0.593; 95% CI, 0.480 to 0.732; P < .001). Consistent treatment effects were observed in patients who were treatment naive in the advanced setting (hazard ratio, 0.577; 95% CI, 0.415 to 0.802), as well as in patients who had received up to one line of prior endocrine therapy for advanced disease (hazard ratio, 0.565; 95% CI, 0.428 to 0.744). Among patients with measurable disease, the overall response rate was 40.9% for the ribociclib plus fulvestrant arm and 28.7% for placebo plus fulvestrant. Grade 3 adverse events reported in ≥ 10% of patients in either arm (ribociclib plus fulvestrant v placebo plus fulvestrant) were neutropenia (46.6% v 0%) and leukopenia (13.5% v 0%); the only grade 4 event reported in ≥ 5% of patients was neutropenia (6.8% v 0%).
CONCLUSION: Ribociclib plus fulvestrant might represent a new first- or second-line treatment option in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer.
DOI: 10.1200/JCO.2018.78.9909
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