2018年英国《柳叶刀》肿瘤学分册发表的MONALEESA-7研究早期分析结果表明，对于激素受体阳性HER2阴性晚期乳腺癌未绝经或围绝经患者，内分泌治疗＋细胞周期蛋白依赖型激酶4和6（CDK4/6）口服抑制剂瑞博西利（LEE011）与内分泌治疗＋安慰剂相比，无进展生存（主要终点）显著延长10.8个月（23.8比13.0个月），复发死亡风险显著减少45%（风险比：0.55，P<0.0001）。
MONALEESA-7: A Phase III Randomized, Double-blind, Placebo-controlled Study of LEE011 or Placebo in Combination With Tamoxifen and Goserelin or a Non-steroidal Aromatase Inhibitor (NSAI) and Goserelin for the Treatment of Premenopausal Women With Hormone Receptor Positive, HER2-negative, Advanced Breast Cancer (NCT02278120)
2019年6月4日，美国麻省医学会《新英格兰医学杂志》在线发表韩国国家癌症中心、首尔大学、延世大学、蔚山大学、中国台湾大学、美国诺华、哈佛大学麻省总医院、洛杉矶加利福尼亚大学、德克萨斯大学MD安德森癌症中心、德国慕尼黑大学、意大利米兰大学欧洲癌症研究所、巴西伊茹伊慈善医院、中国香港肿瘤转化研究组织、墨西哥国家肿瘤中心、西班牙圣胡安德斯皮摩西布罗吉医院、加泰罗尼亚肿瘤研究所、瑞士诺华的MONALEESA-7研究报告，比较了内分泌治疗±瑞博西利治疗激素受体阳性HER2阴性晚期乳腺癌患者的总生存（关键次要终点）。
该国际多中心随机双盲安慰剂对照III期研究于2014年12月17日～2016年8月1日从30个国家或地区188个中心入组年龄18～59岁激素受体阳性HER2阴性晚期乳腺癌未绝经或围绝经女性672例，除了接受内分泌治疗（卵巢功能抑制剂戈舍瑞林＋非甾体芳香酶抑制剂来曲唑或阿那曲唑495例或他莫昔芬177例）还随机分组接受瑞博西利335例或安慰剂337例。通过分层对数秩检验和生存曲线，对总生存进行分析。
结果，瑞博西利与安慰剂相比：
死亡患者：83例比109例（24.8%比32.3%）
总生存率：70.2%比46.0%（95%置信区间：63.5～76.0比32.0～58.9）
死亡风险：减少29%（风险比：0.71，95%置信区间：0.54～0.95，对数秩检验P=0.00973）
内分泌治疗亚组分析结果表明：
芳香酶抑制剂495例：死亡风险减少30%（风险比：0.70，95%置信区间：0.50～0.98）
他莫昔芬治疗177例：死亡风险减少21%（风险比：0.79，95%置信区间：0.45～1.38）
此外，瑞博西利与安慰剂相比：
接受后续抗肿瘤治疗的患者比例相似（68.9%比73.2%）。
二线治疗期间疾病进展死亡风险较低（风险比：0.69，95%置信区间：0.55～0.87）
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，CDK4/6抑制剂瑞博西利＋内分泌治疗与单用内分泌治疗相比，总生存显著延长。随着随访时间延长，未见新的毒性反应问题。
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洛杉矶加利福尼亚大学 Sara Hurvitz 教授
N Engl J Med. 2019 Jun 4. [Epub ahead of print]
Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer.
Seock-Ah Im, Yen-Shen Lu, Aditya Bardia, Nadia Harbeck, Marco Colleoni, Fabio Franke, Louis Chow, Joohyuk Sohn, Keun-Seok Lee, Saul Campos-Gomez, Rafael Villanueva-Vazquez, Kyung-Hae Jung, Arunava Chakravartty, Gareth Hughes, Ioannis Gounaris, Karen Rodriguez-Lorenc, Tetiana Taran, Sara Hurvitz, Debu Tripathy.
Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine; Yonsei Cancer Center, Yonsei University Health System; Asan Medical Center, University of Ulsan College of Medicine, Seoul; Center for Breast Cancer, National Cancer Center, Gyeonggi-do, Korea; National Taiwan University Hospital, Taipei, Taiwan; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston; Ludwig-Maximilians-University Munich, Munich, Germany; Istituto Europeo di Oncologia, Milan; Hospital de Caridade de Ijuí, CACON, Ijuí, Brazil; Organisation for Oncology and Translational Research, Hong Kong; Centro Oncológico Estatal, Instituto de Seguridad Social del Estado de México y Municipios, Toluca, Mexico; Institut Català d'Oncologia, Hospital de Sant Joan Despí Moisès Broggi, Barcelona; Novartis Pharmaceuticals, East Hanover, NJ; Novartis, Basel, Switzerland; UCLA Jonsson Comprehensive Cancer Center, Los Angeles; University of Texas M.D. Anderson Cancer Center, Houston.
BACKGROUND: An earlier analysis of this phase 3 trial showed that the addition of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor to endocrine therapy provided a greater benefit with regard to progression-free survival than endocrine therapy alone in premenopausal or perimenopausal patients with advanced hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Here we report the results of a protocol-specified interim analysis of the key secondary end point of overall survival.
METHODS: We randomly assigned patients to receive either ribociclib or placebo in addition to endocrine therapy (goserelin and either a nonsteroidal aromatase inhibitor or tamoxifen). Overall survival was evaluated with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods.
RESULTS: A total of 672 patients were included in the intention-to-treat population. There were 83 deaths among 335 patients (24.8%) in the ribociclib group and 109 deaths among 337 patients (32.3%) in the placebo group. The addition of ribociclib to endocrine therapy resulted in significantly longer overall survival than endocrine therapy alone. The estimated overall survival at 42 months was 70.2% (95% confidence interval [CI], 63.5 to 76.0) in the ribociclib group and 46.0% (95% CI, 32.0 to 58.9) in the placebo group (hazard ratio for death, 0.71; 95% CI, 0.54 to 0.95; P=0.00973 by log-rank test). The survival benefit seen in the subgroup of 495 patients who received an aromatase inhibitor was consistent with that in the overall intention-to-treat population (hazard ratio for death, 0.70; 95% CI, 0.50 to 0.98). The percentage of patients who received subsequent antineoplastic therapy was balanced between the groups (68.9% in the ribociclib group and 73.2% in the placebo group). The time from randomization to disease progression during receipt of second-line therapy or to death was also longer in the ribociclib group than in the placebo group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.55 to 0.87).
CONCLUSIONS: This trial showed significantly longer overall survival with a CDK4/6 inhibitor plus endocrine therapy than with endocrine therapy alone among patients with advanced hormone-receptor-positive, HER2-negative breast cancer. No new concerns regarding toxic effects emerged with longer follow-up.
Funded by Novartis
MONALEESA-7 ClinicalTrials.gov number: NCT02278120
DOI: 10.1056/NEJMoa1903765
德克萨斯大学MD安德森癌症中心 Debu Tripathy 教授
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