晚期乳腺癌氟维司群＋蒙娜利莎总生存
瑞博西利（瑞波西利、利波西利、LEE011）属于细胞分裂周期蛋白依赖型激酶（CDK）4和6抑制剂之一，可以阻断乳腺癌细胞有丝分裂周期由DNA合成前期进入DNA合成期。2018年，美国临床肿瘤学会《临床肿瘤学杂志》发表的MONALEESA-3研究第一次中期报告表明，瑞博西利＋氟维司群与氟维司群＋安慰剂相比，治疗激素受体阳性HER2阴性晚期乳腺癌绝经后患者的无进展生存获益显著。
前情提要
2019年12月11日，国际四大医学期刊之首、美国麻省医学会《新英格兰医学杂志》在线发表美国洛杉机加利福尼亚大学、纽约大学、费耶特维尔肿瘤医院、比利时鲁汶大学、列日大学、加拿大不列颠哥伦比亚癌症中心、德国纽伦堡大学、意大利那不勒斯国家肿瘤研究所、米兰国家肿瘤研究所、韩国首尔大学、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、塞维利亚大学、荷兰癌症研究所、法国斯特拉斯堡癌症研究所、瑞士诺华的MONALEESA-3研究第二次中期报告，对瑞博西利＋氟维司群治疗晚期乳腺癌的总生存结局进行了分析。该研究第一作者：Dennis J. Slamon。
MONALEESA-3: Study of Efficacy and Safety of LEE011 in Men and Postmenopausal Women With Advanced Breast Cancer: A Randomized Double-blind, Placebo-controlled Study of Ribociclib in Combination With Fulvestrant for the Treatment of Men and Postmenopausal Women With Hormone Receptor Positive, HER2-negative, Advanced Breast Cancer Who Have Received no or Only One Line of Prior Endocrine Treatment (NCT02422615)
该国际多中心安慰剂双盲随机对照三期临床研究于2015年6月～2016年6月入组激素受体阳性HER2阴性晚期乳腺癌绝经后患者726例，按2∶1的比例随机分入两组：除了氟维司群一线或二线治疗之外，其中484例接受瑞博西利、242例接受安慰剂。通过生存曲线和分层对数秩检验，对总生存进行分析。
结果，中位随访39.4个月期间，275例患者死亡，其中瑞博西利组167例（34.5%）、安慰剂组108例（44.6%）。
瑞博西利＋氟维司群与安慰剂＋氟维司群相比，42个月总生存率：57.8%比45.9%（95%置信区间：52.0～63.2、36.9～54.5），死亡风险显著减少28%（风险比0.72，95%置信区间：0.57～0.92，P=0.00455）。对于大多数亚组患者，总生存获益一致。
根据数据更新，瑞博西利＋氟维司群与安慰剂＋氟维司群相比，一线治疗患者的中位无进展生存：33.6比19.2个月（95%置信区间：27.1～41.3、14.9～23.6）。药物安全性分析无新发现。
因此，该研究结果表明，对于激素受体阳性HER2阴性晚期乳腺癌患者，瑞博西利＋氟维司群与安慰剂＋氟维司群相比，总生存获益显著。
N Engl J Med. 2019 Dec 11. [Epub ahead of print]
Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer.
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, Manu Sondhi, Yingbo Wang, Arunava Chakravartty, Karen Rodriguez-Lorenc, Tetiana Taran, Guy Jerusalem.
David Geffen School of Medicine at UCLA, Los Angeles; Universitair Ziekenhuis Leuven, Leuven; Centre Hospitalier Universitaire Liège and Liege University, Liege, Belgium; British Columbia Cancer Agency, Vancouver, Canada; University Hospital Erlangen, Comprehensive Cancer Center Erlangen-European Metropolitan Region of Nuremberg, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen; Practice for Hematology and Internal Oncology, Velbert, Germany; Istituto Nazionale Tumori Fondazione G. Pascale, Naples; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea; Masaryk Memorial Cancer Institute, Brno, Czech Republic; New York University Langone Health, New York; Instituto de Investigación 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, Universidad de Sevilla, Seville, Spain; Netherlands Cancer Institute-Borstkanker Onderzoek Groep Study Center, Amsterdam; Highlands Oncology Group, Fayetteville, AR; Institut Régional du Cancer, Strasbourg, France; Novartis Pharmaceuticals, East Hanover, NJ; Novartis Pharma, Basel, Switzerland.
BACKGROUND: In an earlier analysis of this phase 3 trial, ribociclib plus fulvestrant showed a greater benefit with regard to progression-free survival than fulvestrant alone in postmenopausal patients with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Here we report the results of a protocol-specified second interim analysis of overall survival.
METHODS: Patients were randomly assigned in a 2:1 ratio to receive either ribociclib or placebo in addition to fulvestrant as first-line or second-line treatment. Survival was evaluated by means of a stratified log-rank test and summarized with the use of Kaplan-Meier methods.
RESULTS: This analysis was based on 275 deaths: 167 among 484 patients (34.5%) receiving ribociclib and 108 among 242 (44.6%) receiving placebo. Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant. The estimated overall survival at 42 months was 57.8% (95% confidence interval [CI], 52.0 to 63.2) in the ribociclib group and 45.9% (95% CI, 36.9 to 54.5) in the placebo group, for a 28% difference in the relative risk of death (hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P=0.00455). The benefit was consistent across most subgroups. In a descriptive update, median progression-free survival among patients receiving first-line treatment was 33.6 months (95% CI, 27.1 to 41.3) in the ribociclib group and 19.2 months (95% CI, 14.9 to 23.6) in the placebo group. No new safety signals were observed.
CONCLUSIONS: Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant in patients with hormone-receptor-positive, HER2-negative advanced breast cancer.
Funded by Novartis
MONALEESA-3 ClinicalTrials.gov number: NCT02422615
DOI: 10.1056/NEJMoa1911149