蒙娜利莎Ⅱ：激素受体阳性晚期乳腺癌的利布昔利布一线疗法
内分泌疗法是激素受体（HR）阳性晚期乳腺癌的标准一线疗法，但是绝大多数患者出现内分泌疗法耐药导致治疗失败。周期蛋白依赖性激酶（CDK）4/6抑制剂可延缓或克服内分泌疗法耐药。
2016年10月7日，美国麻省（马萨诸塞州）医学会官方期刊《新英格兰医学杂志》在线发表美国、以色列、新加坡、荷兰、法国、德国、意大利、英国、捷克、澳大利亚、丹麦、俄罗斯、西班牙、挪威、中国台湾、瑞士诺华的MONALEESA-2（Mammary ONcology Assessment of LEE011's Efficacy and SAfety）双盲、随机、安慰剂对照、Ⅲ期临床研究中期分析报告，评价了CDK4/6抑制剂利布昔利布（利泊昔布）＋来曲唑，对比安慰剂＋来曲唑，用于HR阳性、HER2阴性晚期乳腺癌患者一线治疗的有效性与安全性。
该研究（NCT01958021）将668例既往未接受过针对晚期疾病全身治疗、激素受体阳性、HER2阴性、乳腺癌复发或转移的绝经女性，按1∶1随机接受利布昔利布（每天600mg×3周、休1周）＋来曲唑（每天2.5mg）或安慰剂＋来曲唑。
主要终点为研究者评定的无进展生存，次要终点包括：总生存、总有效率和安全性。在出现243例进展事件之后进行既定的中期分析。在243例患者疾病进展或死亡后，按计划于数据截止日期2016年1月29日进行中期分析。预先规定的优势标准要求风险比为≤0.56、P＜1.29×10-5。
经过中位随访15.3个月，结果发现：
利布昔利布组的无进展生存显著优于安慰剂组（风险比：0.56，95%置信区间：0.43～0.72，P=3.29×10-6）。
18个月后，利布昔利布组、安慰剂组的无进展生存率分别为63.0%、42.2%（95%置信区间：54.6～70.3、34.8～49.5）。
在基线时病灶可测量的患者中，总有效率分别为52.7%、37.1%（P＜0.001）。
在任一组患者超过10%报告的常见3或4级不良事件为中性粒细胞减少（59.3%比0.9%）和白细胞减少（21.0%比0.6%），不良事件所致停药率分别为7.5%、2.1%。
因此，作者认为在接受初始全身治疗的HR阳性、HER2阴性晚期乳腺癌患者中，接受利布昔利布＋来曲唑者的无进展生存期明显长于接受安慰剂＋来曲唑者，前者的骨髓抑制率较高。
2016年10月8日，在丹麦哥本哈根召开的欧洲肿瘤内科学会（ESMO）年会也公布了该研究摘要（LBA1）。
N Engl J Med. 2016 Oct 7. [Epub ahead of print]
Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer.
Gabriel N. Hortobagyi, Salomon M. Stemmer, Howard A. Burris, Yoon-Sim Yap, Gabe S. Sonke, Shani Paluch-Shimon, Mario Campone, Kimberly L. Blackwell, Fabrice André, Eric P. Winer, Wolfgang Janni, Sunil Verma, Pierfranco Conte, Carlos L. Arteaga, David A. Cameron, Katarina Petrakova, Lowell L. Hart, Cristian Villanueva, Arlene Chan, Erik Jakobsen, Arnd Nusch, Olga Burdaeva, Eva-Maria Grischke, Emilio Alba, Erik Wist, Norbert Marschner, Anne M. Favret, Denise Yardley, Thomas Bachelot, Ling-Ming Tseng, Sibel Blau, Fengjuan Xuan, Farida Souami, Michelle Miller, Caroline Germa, Samit Hirawat, Joyce O'Shaughnessy.
University of Texas M.D. Anderson Cancer Center, Houston; Texas Oncology-Baylor Charles A. Sammons Cancer Center; U.S. Oncology Network, Dallas, Texas; Davidoff Center, Rabin Medical Center, Tel Aviv University, Tel Aviv; Sheba Medical Center, Ramat Gan, Israel; Sarah Cannon Research Institute, Vanderbilt-Ingram Cancer Center, Tennessee Oncology, Nashville; National Cancer Center Singapore, Singapore; Netherlands Cancer Institute, BOOG Study Center, Amsterdam; Institut de Cancérologie de l'Ouest/René Gauducheau, Saint-Herblain, Institut Gustave Roussy, Université Paris Sud, Villejuif, University Hospital of Besancon, Besancon, Centre Léon Bérard, Lyon, France; Duke University Medical Center, Durham, NC; Dana-Farber Cancer Institute, Boston; University of Ulm, Ulm, Onkologische Praxis, Velbert, University of Tübingen, Tübingen; Joint Practice for Interdisciplinary Oncology and Hematology, Freiburg, Germany; Tom Baker Cancer Centre, Calgary, AB, Canada; University of Padua, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, Padua, Italy; Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh; Masaryk Memorial Cancer Institute, Brno, Czech Republic; Florida Cancer Specialists-Sarah Cannon Research Institute, Fort Myers; Breast Cancer Research Centre-Western Australia, Curtin University, Perth, Australia; Department of Oncology, Vejle Hospital, Vejle, Denmark; Arkhangelsk Clinical Oncology Dispensary, Arkhangelsk, Russia; Hospital Universitario Virgen de la Victoria, Institute of Biomedical Research in Málaga, Málaga, Spain; Oslo University Hospital, Oslo; Virginia Cancer Specialists, Arlington; Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan; Rainier Hematology-Oncology, Northwest Medical Specialties, Puyallup, WA; Novartis Pharmaceuticals, East Hanover, NJ; Novartis Pharma, Basel, Switzerland.
BACKGROUND: The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2).
METHODS: In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29×10-5.
RESULTS: The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29×10-6 for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively.
CONCLUSIONS: Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group.
Funded by Novartis Pharmaceuticals.
ClinicalTrials.gov number: NCT01958021
PMID: 27717303
DOI: 10.1056/NEJMoa1609709